Airborne indoor allergen serine proteases and their contribution to sensitisation and activation of innate immunity in allergic airway disease

Xuan Ouyang, James A. Reihill, Lisa E.J. Douglas, S. Lorraine Martin
European Respiratory Review 2024 33: 230126; DOI: 10.1183/16000617.0126-2023

Abstract

Common airborne allergens (pollen, animal dander and those from fungi and insects) are the main triggers of type I allergic disorder in the respiratory system and are associated with allergic rhinitis, allergic asthma, as well as immunoglobulin E (IgE)-mediated allergic bronchopulmonary aspergillosis. These allergens promote IgE crosslinking, vasodilation, infiltration of inflammatory cells, mucosal barrier dysfunction, extracellular matrix deposition and smooth muscle spasm, which collectively cause remodelling of the airways. Fungus and insect (house dust mite and cockroaches) indoor allergens are particularly rich in proteases. Indeed, more than 40 different types of aeroallergen proteases, which have both IgE-neutralising and tissue-destructive activities, have been documented in the Allergen Nomenclature database. Of all the inhaled protease allergens, 85% are classed as serine protease activities and include trypsin-like, chymotrypsin-like and collagenolytic serine proteases. In this article, we review and compare the allergenicity and proteolytic effect of allergen serine proteases as listed in the Allergen Nomenclature and MEROPS databases and highlight their contribution to allergic sensitisation, disruption of the epithelial barrier and activation of innate immunity in allergic airways disease. The utility of small-molecule inhibitors of allergen serine proteases as a potential treatment strategy for allergic airways disease will also be discussed.

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Introduction

Sensitisation to airborne allergens is the main risk factor for allergic respiratory disease, including allergic asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) and immunoglobulin E (IgE)-mediated components of allergic bronchopulmonary aspergillosis (ABPA), the prevalence of which has increased globally over the last number of decades [1]. In 2019, asthma was reported to affect an estimated 262 million people worldwide and caused 455 000 deaths [2]. AR, characterised by anterior or posterior rhinorrhoea, sneezing, nasal blockage and/or itching of the nose, as well as a number of non-nasal symptoms such as allergic rhinoconjunctivitis, post-nasal drip and cough, affects an estimated 25% of children and 40% of adults globally [3]. CRS, a complex, heterogeneous inflammatory disease of the sinonasal mucosa, has a prevalence of 10.9% in the EU and 12.3% in the USA across all age groups [4]. ABPA is a fungal infection of the lung that affects severe asthmatics, but also individuals with cystic fibrosis (CF). It is characterised by evidence of allergy to the antigens of Aspergillus (Asp.) species upon its colonisation of the airways. The most common airborne fungus is Asp. fumigatus [5]. Although these conditions may exist independently from one another, many asthmatics (40–90%) will also show symptoms of AR, CRS or ABPA [6]. Such comorbidity is frequently associated with more frequent asthmatic attacks, leading to a greater number of emergency room visits as well as increased asthma-related hospitalisations and medical costs [7]. Avoidance of asthma triggers such as airborne allergens, in addition to adequate inhaled medication, is therefore critically important in the management of asthma symptoms.

A hallmark of allergic airways disease is the presence of raised IgE against common aeroallergens. Exposure to an allergen induces the generation of a specific IgE that binds to the high-affinity IgE receptor (FcεRI) on mast cells and basophils. A second exposure thus initiates an IgE-mediated hypersensitivity. The antigen binds to the IgE–FcεRI complex that is already present on the surfaces of mast cells and basophils. The crosslinking of the antigen-triggered bound IgE–FcεRI complex results in degranulation of mast cells and increased secretion of histamine, leukotrienes, heparin, proteases and other inflammatory mediators. This leads to elevated vascular permeability, peripheral vasodilation and smooth muscle contraction [8]. Allergens with proteolytic activity not only cause atopic effects, but also damage epithelial barrier integrity enabling allergens to directly interact with the immune system. This promotes allergic inflammation and subsequent secondary allergen sensitisation and other infection [9].

Herein, specific allergen serine proteases were identified from the Allergen Nomenclature (as listed by the World Health Organization and International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature Sub-Committee) and MEROPs (peptidases) databases, which allowed a search to be performed on PubMed to ascertain their association with inflammatory or cellular changes in relevant cell and animal models or their clinical relevance to the progression of allergic asthma, AR and CRS. In particular, we highlight the allergenicity and proteolytic effect of indoor serine protease allergens from fungi (to include moulds and yeast) and arthropods (mites and cockroaches) and their contribution to allergic sensitisation, disruption of the epithelial membrane barrier and activation of innate immunity in allergic airways disease. The utility of small-molecule inhibitors of the allergen serine proteases as a potential treatment strategy for allergic airways disease is also discussed.

Activity and source of indoor serine protease allergens

Common airborne allergens, such as fungi, house dust mites (HDMs) and cockroaches, are rich in serine protease activities that are highly involved in the development of allergic inflammation and barrier dysfunction in the airways. Serine proteases are characterised by the presence of a primary serine residue in the catalytic triad of their active site, which acts as a nucleophile to catalyse the hydrolysis of peptide bonds [10]. There are more than 40 types of aeroallergen serine proteases documented in the Allergen Nomenclature database created by the WHO/IUIS Allergen Nomenclature Sub-Committee, including subtilisin-like, elastinolytic, trypsin-like, chymotrypsin-like and collagenolytic serine proteases [11]. Table 1 summarises the source, biochemical classification, size, IgE binding ability and cross-reactivity of all the allergen serine proteases documented in the peptidase (MEROPS) and Allergen Nomenclature databases.

View this table:
TABLE 1

Serine proteases associated with airborne allergens as documented in the peptidase (MEROPS) and Allergen Nomenclature databases

Fungi

Fungi predominantly contain elastinolytic and subtilisin-like serine proteases. The S1 specificity pocket of elastinolytic serine proteases are gated with two bulkier valine residues, which only allows them to cleave peptides containing amino acids with small side chains (e.g. alanine, serine, leucine and valine) in the complementary P1 position. Subtilisin-like serine proteases are an example of convergent evolution and share a similar active site (His-Asp-Ser) with chymotrypsin, i.e. the catalytic triad that also enables the formation of the oxyanion hole required for substrate hydrolysis. A difference, however, is that the oxyanion hole in the active site of subtilisin-like serine proteases is not formed by the peptide backbone but is assembled by the amine group from the side chain of an asparagine residue. Some of the elastinolytic serine proteases not only contains elastase activities, but also show homology to subtilisin-like protease, especially Asp fl 13, Asp f 13, Asp o 13 and Asp v 1 found in Asp. species.

Insects (arthropods)

Within the animal kingdom, arthropods (mite and cockroach) shed allergenic proteins in their egg casings, skin casts, whole bodies, secretions and faecal materials which can then become airborne. These proteins are rich in trypsin-like (TLP) and chymotrypsin-like serine proteases (CTLP) (table 1). TLPs in contrast to elastinolytic proteases, cleave long and positively charged peptide bonds (e.g. arginine and lysine) while CTLPs cleave peptide residues with aromatic or long, nonpolar side chains (e.g. phenylalanine or leucine). Der p 1, a cysteine protease, is the most abundant protease found in mite faecal pellets and is a major inducer of the IgE allergic response. Der p 1 activity is also pivotal to the activation of several HDM serine proteases, Der p 3, 6 and 9, that further contribute to allergenicity [111]. The impact of Der p 1 in allergic airway disease has been extensively reviewed by other researchers [112, 113].

Per a 10 is an abundant TLP found in the American cockroach (Periplaneta (Per.) americana) that has been found to alter immune signalling in the airways [114]. Bla g 2 is a potent allergen isolated from the German cockroach (Blattella (Bla.) germanica) that upon further characterisation was determined to be an inactive aspartic protease (therefore excluded from table 1). Pro-inflammatory effects of Bla. germanica extract on airway epithelial cells have, however, been attributed to three biochemically distinct serine TLP activities (designated E1, E2 and E3, but not listed in the WHO/IUIS Allergen Nomenclature) with a 57–71% sequence identity to Per a 10 and able to trigger both Ca2+ and mitogen-activated protein kinase signalling via activation of protease-activated receptor (PAR)-2 [93].

Mammals

Only a very small number of serine proteases are derived from the dander of mammals, such as dogs (Can f 5) and cats (Fel d 1). Can f 5 is a kallikrein expressed in the prostate and hence present only in the urine of male dogs with levels reduced upon neutering; Can f 5 has cross-reactivity with human prostate-specific antigen. It may also be present in extracts of dog hair and dander [31]. Studies have shown that the 18-kDa form of Fel d 1 is capable of degrading gelatin (denatured collagen), can cleave the A chain of plasma fibronectin and may be inhibited by the serine protease inhibitors aprotinin and N-p-tosyl-L-lysine chloromethyl ketone (TLCK). It does, however, lack a serine peptidase catalytic triad, which suggests that the inhibitory action of aprotinin and TLCK may be due to noncatalytic site interactions [115].

The ability of airborne serine protease allergens to compromise the epithelial barrier, create a pro-inflammatory environment and to induce airway remodelling, through cleavage of tight junction (TJ) and extracellular matrix (ECM) proteins and regulation of airway epithelial, immune and smooth muscle cells, is summarised in figure 1 and will be discussed in detail in the various sections below.

FIGURE 1
FIGURE 1

Allergenic and proteolytic activities of serine proteases from airborne allergens induce airway remodelling and promote a pro-inflammatory environment through regulation of airway epithelial, immune and smooth muscle cells, cleavage of tight junctions (TJs) and degradation of extracellular matrix (ECM) proteins. Initial damage of TJ proteins of airway epithelial cells is caused by allergen proteolytic activities triggering various interactions with immune cells. The synergistic pro-inflammatory effects of epithelial and dendritic cells (DCs) promote formation of a type 2 environment, as characterised by increased expression of interleukin (IL)-4, IL-5, IL-9, IL-13 and IL-23 by Th2 cells, accompanied by Th17 inflammatory responses which contributes to disruption of airway epithelium. This involves airway dehydration, excess mucus production, goblet cell hyperplasia and deciliation. An imbalance of protease and anti-protease activities in the ECM is characterised by increased elastase, tryptase and matrix metalloproteinase (MMP)-9 expression accompanied by reduced α1 antitrypsin (A1AT) and serine protease inhibitor Kazal-type 5 (SPINK5) expression. The alteration of ECM components also includes elevated growth factors (transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF)), therefore contributing to epithelial–mesenchymal transition and airway smooth muscle (ASM) hypertrophy and hyperplasia. CXCL1: chemokine ligand 1; CCL20: chemokine ligand 20; COX-2: cyclooxygenase-2; DAMPs: damage-associated molecular patterns; GM-CSF: granulocyte macrophage–colony-stimulating factor; IgE: immunoglobulin E; ILC2: type 2 innate lymphoid cell; PGE-2: prostaglandin E2; Tfh: T-follicular helper cells; Th2: T-helper 2 cells; Th17: T-helper 17 cells; TNF-α: tumour necrosis factor-α; TSLP: thymic stromal lymphopoietin; UA: uric acid. Figure created with BioRender.com.

Allergen serine proteases and airway epithelial barrier dysfunction

Disruption of TJs and effects on epithelial permeability

The airway epithelium acts as the first line of defence for the lungs and provides a physical, chemical and immunologic barrier in response to invasion of external environmental factors. Although repeated exposure to potentially harmful external factors can damage the pseudostratified structure of the epithelium, a slow but continuous process of renewal and repair helps to maintain airway homeostasis [116]. The pseudostratified epithelium is formed by different types of airway epithelial cells, including suprabasal, club, goblet, deuterosomal and ciliated cells, with rare cell types such as ionocytes, pulmonary neuroendocrine cells, tuft cells and “hillock” cells also present [117].

Mucociliary clearance mechanisms

An appropriate balance of mucosecretory and ciliated cells is vital for the effectiveness of mucociliary clearance (MCC) and underlies the physical innate defence mechanisms of the airways. The cilia are bathed by an airway surface liquid (ASL) comprising two layers, an upper mucus layer and a lower periciliary layer (PCL), and serves to protect the barrier function of the airway epithelium and the lower airways from harmful environmental substances. Mucin glycoproteins within the mucus layer physically trap inhaled particles while the aqueous PCL, whose volume is regulated by a balance of Na+ and Cl− transport, provides airways hydration and lubrication to promote the upward movement of the mucus layer via synchronised ciliary beating [118]. A serine protease from HDMs (trypsin-like and chymotrypsin-like protease) has been reported to increase apical Cl− secretion through calcium-activated chloride channels and CF transmembrane conductance regulator (CFTR), which is associated with the watery rhinorrhoea commonly seen in allergic airway diseases [119]. The activation of PAR-2 by proteases can also lead to an increase in cilia beating [120]. The impact of other types of allergen serine proteases, such as subtilisin-like and elastinolytic serine proteases on MCC, however, remains unknown. Bacterial elastase-like protease activities from Pseudomonas aeruginosa have been shown to disrupt coordinated secretion involving CFTR, PAR-2 and vasoactive intestinal peptide receptor in air–liquid interface (ALI) culture of Calu-3 cells, so it is possible that the elastase-like allergen serine proteases also contribute to the reduction of fluid secretion in serous cells.

TJs and the epithelial barrier

The barrier function of the epithelium is maintained by TJs between cells that are assembled by the scaffolding zonula occludens (ZO) family of proteins on the apical epithelium. TJs maintain the polarity of the airway epithelium, act as a bridge for cell–cell connections and communication, and play a critical role in limiting paracellular transport. The family of integral membrane proteins, including claudins and junctional adhesion molecules (JAMs), as well as occludins, tricellulin and marvel D3, is involved in the regulation of paracellular permeability. A charge-selective small-pore pathway is constructed by claudins to control ion conductance, while JAMs are involved in the regulation of macromolecule permeability [121]. At the basolateral membranes of epithelial cells, major intercellular adhesive junctions are formed by desmosomes creating a supracellular scaffold that enable the cell–cell contacts essential to tissue architecture [122]. Desmosomes are formed by specialised members of the cadherin family and associated cytoskeletal-linking proteins. They provide mechanical resilience to tissues and anchor intermediate filaments to the plasma membrane.

The effect of allergen serine proteases on epithelial permeability

Nearly all allergen serine proteases have been confirmed to have damaging proteolytic effects on TJs that result in the integrity of the epithelial barrier being compromised (figure 2). This includes fungal proteases, such as Alternaria (Alt.) alternata [123] and Asp. fumigatus serine proteases [124], Penicillium (Pen.) chrysogenum Pen ch 13 [125, 126], as well as HDM serine proteases [127, 128]. Serine proteases (groups 3, 6, 9) from HDM faecal pellets can cleave TJ proteins (occludins, ZO-1 and, to a lesser extent, E-cadherin) and concentrate desmosomal puncta (breaches), leading to high levels of epithelial permeability [127]. A study comparing the effect of HDM cysteine (Der p 1) and serine (Der p 6) proteases on ALI-polarised cultures of the lung epithelial cell line BEAS-2B demonstrated that the CTLP Der p 6 led to an increase in epithelial permeability [128]. In addition, degradation of occludin, ZO-1 and E-cadherin in Pen c 13 sensitised mice led to a progressive increase in epithelial permeability [126]. An increased production of mitochondrial reactive oxygen species (ROS) at the time of exposure to Asp. proteases also contributed to the epithelial cell barrier function being damaged, leading to pathological changes [129].

FIGURE 2
FIGURE 2

Allergen serine proteases impair airway epithelial barrier function. Allergen serine proteases from house dust mites, as well as Penicillium and Aspergillus species can cleave tight junction (TJ) proteins (zonula occludens-1 (ZO-1), junctional adhesion molecules (JAMs), occludin, claudin) and adherens junctions (AJs) (e.g. E-cadherin) and can create puncta in desmosomes. Production of mitochondrial reactive oxygen species (ROS) in response to exposure to Aspergillus proteases can also contribute to the epithelial cell barrier function being damaged, leading to pathological changes. Figure created with BioRender.com.

Stimulation of a pro-inflammatory response by allergen proteases

Alarmin and type 2 inflammatory response

Allergen serine proteases stimulate the production of epithelial and immune cell-derived inflammatory mediators which contribute to type 2 inflammation (figure 1). In particular, epithelial “alarmin” cytokines such as interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP), released in response to tissue injury, play an important role in type 2 asthma. IL-33, which is a cytokine belonging to the IL-1 family, mainly targets IL-1-like receptor (ST2) on immune cells, especially tissue-resident mast cells, type 2 innate lymphoid cells (ILC2s) and tissue regulatory T-cells that express high levels of ST2 [130, 131]. Serum levels of IL-33 have been reported to be higher in patients with allergic and eosinophilic asthma phenotypes compared to nonallergic and noneosinophilic phenotypes [132]. In addition, allergen inhalation triggers upregulation of ST2 expression in eosinophils from blood and sputum derived from allergic asthma patients [133]. Exposure to Alt. alternata serine proteases led to the rapid release of IL-33 in lung epithelial cells from Alt. alternata challenged mice and simultaneously, also stimulated neutrophilia, eosinophilia and recruitment of tissue macrophages, as well as elevated IL-13 expression but had no effect on IL-5 levels [134].

Serine proteases from HDM have been reported to increase epithelial IL-33, TSLP and IL-25 secretion, resulting in activation of ILC2s, which produce IL-5, IL-9 and IL-13, in addition to IL-5 from eosinophils [135, 136]. Specifically, trypsin-like serine proteases have been identified to be the main allergen component of HDMs leading to the increased secretion of IL-33 and TSLP from asthma human primary bronchial epithelial cells (hPBECs) [137]. Upon exposure of epithelial cells to allergen proteases (fungi, cockroaches and mites), caspase-8 is activated via a novel signalling hub, the caspase-8 activating ripoptosome, a protein complex which consists of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Fas-associated via death domain and pro-caspase-8 [138, 139]. The liberated active caspase-8 then facilitates activation of caspases-3 and -7 (cleavage site at residues D175 and D178), which, in turn, directly promotes potentiation and maturation of IL-33 that is co-released with histone [138]. Secretion of IL-33 is then completed by neo-form murine amino-terminal p40 fragment gasdermin D, which promotes pore formation in the cell membrane [140]. The RIPK1–caspase 8 ripoptosome complex is, therefore, an allergen-sensing platform able to detect a diverse range of allergic stimuli. However, the actual signalling pathways, such as the role of PARs (see the section entitled “PARs”) and canonical pattern recognition receptors (PRRs) (see the section entitled “PRRs”), may lead to its activation have yet to be established [138]. Full-length IL-33 precursor (30 kDa) can also be directly processed by allergen serine proteases from HDMs, Alt. alternata, Asp. fumigatus, Asp. oryzae and cockroaches to generate mature IL-33 forms (18–21 kDa) [141]. Of note, mature IL-33 forms can have biological activity 10–30 times higher than that of their precursor and are thus capable of driving a cytokine storm [142]. The role of allergen proteases in the processing and maturation of IL-33 is summarised in figure 3.

FIGURE 3
FIGURE 3

Allergen serine proteases play a role in the maturation and secretion of interleukin (IL)-33 contributing to the type 2 inflammatory response. Allergen proteases can either directly process the full-length IL-33 (30 kDa) to mature IL-33 forms (18–21 kDa) or IL-33 can be potentiated and matured via the caspase-8 activating ripoptosome (a protein complex consisting of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Fas-associated via death domain (FADD) and pro-caspase-8). Ripoptosome activation is a pre-determined series of molecular events that starts with rapid RIPK1 phosphorylation and pro-caspase-8 activation, followed by degradation of RIPK1 and activation of caspases-3 and -7. Stress granule (SG) assembly permits the transportation of full-length (FL)-IL-33 from the nuclear compartment to the cytoplasm. The active caspases-3 and -7 then convert intracellular precursor IL-33 moieties with histone bonded into active mature (m)-IL-33. The involvement of protease activated receptors (PARs) and pattern recognition receptors (PRRs) in the initial signalling of this process remains unclear. Simultaneously, mature caspase-8 converts GSDMD-NT (consisting of an N-terminal domain (NTD) containing 242 amino acids) into neo-form murine amino-terminal p40 fragment gasdermin D (GSDMD), which leads to membrane pore formation to facilitate the release of m-IL-33. FL-IL-33 consists of three parts. The residues of amino acids from 1 to 65 are the nuclear domain, 65–112 are the protease sensor domain, which allows cleavage by endo-/exogenous proteases, and 112–270 are the IL-1-like domain containing the caspase cleavage sites at D175 and D178. Active IL-33 can then activate immune cells expressing IL-1-like (ST2) receptors (i.e. type 2 innate lymphoid cells (ILC2), mast cells, eosinophils, T-helper 2 (Th2) cells and dendritic cells (DCs)) to propagate a type 2 inflammatory response. Figure created with BioRender.com.

Other alarmins that are increased upon the exposure of human bronchial epithelial cells (HBECs) to serine proteases from HDMs, Artemisia vulgaris, Betula pendula and Alt. alternata, include ATP and uric acid (UA) [143]. Moreover, another study suggested that Alt. alternata and HDM serine proteases may possibly intensify the type 2 immune response through triggering DNA release from HBECs. The underlying mechanism involves the induction of ROS production by Alt. alternata and the subsequent apical release of nuclear and mitochondrial DNA. These DNAs serve as alarmins, which induce Ca2+ uptake via ATP release and subsequent activation of P2X purinergic receptors. The increase of intracellular Ca2+ concentration also elevates expression of the proprotein convertase furin, which promotes the maturation of the nuclear DNA fragmentation modulator, caspase-3 [144].

Other pro-inflammatory mediators

Aeroallergen serine proteases also promote secretion of other inflammatory mediators from airway epithelial cells. Alt. alternata serine proteases induced IL-8 and tumour necrosis factor-α (TNF-α) production from 16HBE cells, although reduced IL-8 production was observed in asthma ALI primary HBECs in response to Alt. alternata compared to healthy donors [123]. Protease activities of Pen ch 13 decreased cluster of differentiation (CD) 44 expression and increased expression of inflammatory mediators such as IL-8, prostaglandin-E2, cyclo-oxygenase-2 and transforming growth factor-β1 from HBEC lines (A549 and 16HBE14o-) and primary HBECs [125]. Additionally, Pen ch 13 has also been reported to stimulate histamine release from basophils of asthmatic patients [23] and IL-8 from HBECs [89]. Serine proteases from German cockroach induced elevation of chemokine (C-C motif) ligand 20 (CCL20) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generation in the airways leading to the deployment and/or differentiation of myeloid dendritic cells (DCs) [145].

In terms of HDM allergens, the CTLP Der p 6 induces IL-6 production but decreases IL-8 and GM-CSF production in airway epithelial cells [128]. A similar effect on IL-6 production was observed with the collagenolytic serine TLP Der p 9. Der p 9 and Der p 3 also contributing to GM-CSF and eotaxin release from HBECs [66]. Treatment of primary HBECs and the epithelial cell line BEAS-2B by Der p 1 and Der p 9 induced both concentration- and time-dependent increases in the release of GM-CSF, IL-6 and IL-8 [146]. Der f 3 facilitates IL-6, IL-8, GM-CSF, IL-1β, chemokine ligand 1 and CCL20 production from HBECs, possibly contributing to the development of the T-helper (Th)-17 and Th2/Th17 mixed asthma endotypes [56]. An in vivo study further confirmed that HDM proteases trigger the generation of a chemokine, cytokine and oxidant response from airway epithelial cells, which activates IL-17A/IL-17R signalling, resulting in an increase in neutrophilic inflammation [147].

Allergen serine proteases as Th2 adjuvants

Dendritic and Th cell recruitment

An increase in epithelial permeability caused by active allergen serine proteases (see the section entitled “TJs and the epithelial barrier”) permits their access to the sub-epithelial layer stimulating DC recruitment and allergic sensitisation. Fungal serine protease Asp f 13 (also called alkaline protease 1) can disrupt the TJs of bronchiolar epithelial club cells upon stimulation of mechanosensor transient receptor potential (TRPV) 4 channels, followed by elevation of intracellular Ca2+ [148]. Subsequently, Ca2+-regulated calcineurin can activate nuclear factor of activated T-cells, thus contributing to the production of an allergic, inflammation-driven cytokine and chemokine storm through employment of DCs and Th2 cells [148, 149]. DCs also trigger generation of T-follicular helper (Tfh) 1 and 2 cells and polarised Th2 cells.

Allergen serine proteases drive a Th2-adjuvant occurrence and altered airway remodelling

Th2-cells generate cytokines that are known to be involved in airway remodelling in asthma. Additionally, IL-4 secreted by Tfh cells stimulates IgM+ naive B-cells to change to IgG+ memory B-cells or IgE+ memory B-cells via class switch recombination (CSR). Basophils, mast cells and ILC2s also generate Th2 cytokines and contribute to the development of type 2 high airway diseases [150, 151].

Th2 adjuvant occurrence

Due to the abundance of proteolytic and sensitised activities in allergens, a growing number of studies recognise their ability to facilitate the Th2 adjuvant occurrence of the airway allergic inflammatory response. Alt. alternata serine proteases induce cell infiltration in murine airways [152]. Per a 10 from Per. americana induces DCs to a Th2-biased polarisation characterised by increased CD86 and TNF superfamily member 4 (also known as OX40 L) expression and reduced CD40 expression, which promotes a decrease of IL-12 and an elevation of IL-23, IL-13 and IL-4 expression in a murine lung model [15, 153–155]. Elevation of IgE and IgG1 in serum and an increased level of IL-4 and IL-5 in bronchoalveolar lavage fluid (BALF) and splenocyte culture supernatant was observed from mice challenged with Cur l 1 from C. lunata compared to an inactive Cur l 1 group [156]. Likewise, Pen c 13 induced elevated expression of Pen c 13-specific IgE and IgG1 in mice and increased IL-4, IL-5 and IL-13 production in Pen c 13 treated splenocytes [126].

Type 2 environment and altered airway remodelling

The type 2 environment with elevation of IL-4 and IL-13 contributes to alteration of airway epithelial remodelling, including goblet cell metaplasia and deciliation [150, 157], and drives excessive goblet cell differentiation due to disruption of the mucin (MUC) 5AC and MUC5B balance in the airway, a common feature found in asthma, AR and CRS. Overproduction of MUC5AC induces increased ASL viscosity and diminished ciliary beating that alongside airway dehydration disrupts MCC [116]. The increased expression of MUC5AC has also been observed in an HBEC line (NCI-H292) treated with Asp. fumigatus, an effect that was diminished by serine protease inhibitors [158].

Allergen serine proteases contribute to dysregulated airways remodelling in allergic asthma

Allergen proteases can alter ECM components to promote airway remodelling

ECM structures in healthy airways

In healthy tissues, a thin layer of ECM called the basement membrane (BM) is located on the basal side of the epithelium and is responsible for separating the epithelium from underlying connective tissue to maintain the stability of the overall airway structure. Below the BM, a fibril-like network of ECM, which acts as indispensable scaffold for maintaining tissue integrity, surrounds the cells and connects them within a biological three-dimensional structure in the airways smooth muscle (ASM) layer [159]. The upper airway is typically resistant to environmental insults and can mount an inflammatory response in concert with effective airway injury repair processes [160]. The BM and ECM are composed of a variety of matrix proteins including collagen I, III and V, elastins, proteoglycans, fibronectin, biglycan, lumican, versican, decorin, and tenascin [161].

Structural changes in asthmatic airways

Structural changes in the airways have long been recognised as the main feature of asthma and are also observed in other upper airway diseases. Key features observed in allergen-associated airway diseases including AR, CRS with nasal polyps (CRSwNP) and allergic asthma include epithelial shedding, excessive goblet cell differentiation, BM thickening in both the upper and lower airways, and an active epithelial–mesenchymal trophic unit within the epithelial layer. Mucus gland hypertrophy and ECM deposition in the submucosal layer may also be observed in CRSwNP and allergic asthma, while these features can remain normal in AR [160]. Asthma is also characterised by ASM hypertrophy, which is a more severe phenotype of airway remodelling.

Airways remodelling in asthmatic airways

Host matrix metalloproteinases (MMPs) (a group of collagenases and gelatinases) are the major proteases responsible for the normal remodelling of the ECM to achieve effective organisational and morphological changes. Damage of the epithelial barrier by allergen serine proteases during allergen sensitisation can stimulate an increased expression of adhesion molecules and growth factors to promote tissue repair. The deposition of ECM proteins is, therefore, a sign of epithelial restoration.

Elevation of MMP-9 (gelatinase B) levels have, however, been observed in BALF from patients with severe asthma [162]. Allergen serine proteases from Asp. fumigatus, Pen. chrysogenum and Asp. versicolor can induce the release of pro-MMP-9 from human leukaemia monocytic cells (THP-1) [163] and HBECs [164]. The inactive form of pro-MMP-9 generated by eosinophils, neutrophils, alveolar macrophages and airway epithelial cells can then be cleaved by endogenous or exogenous proteases to generate active MMP-9 [165]. For instance, serine proteases from cockroach frass and HDMs can cleave pro-MMP-9 in a dose- and time-dependent manner that is abrogated by pre-treating frass with an inhibitor of serine, but not cysteine protease activity, and can neutralise the endogenous, highly protective, neutrophil elastase (NE) inhibitor α1-antitrypsin (AAT; also known as α1-proteinase inhibitor or SERPIN-A1) [166]. The much higher serine protease activities in cockroaches are also reflected in a heightened ability to activate endogenous pro-MMP-9, compared to HDMs [164]. Allergen proteases, therefore, contribute to the negative skewing of the protease–antiprotease balance observed in allergic asthma that increases the risk of irreversible lung tissue damage [164].

Smooth muscle constriction and airway hyperresponsiveness

Epithelial barrier dysfunction, alteration of ECM components and inflammatory cell infiltration contribute to a continuous cycle of remodelling within the asthmatic airway. This is also driven by raised levels of pro-inflammatory cytokines and chemokines, growth factors as well as contractile agonists (histamine, acetylcholine and substance P), which facilitate ASM cell hypertrophy and fibroblast hyperactivity. An increased deposition of ECM, epithelial and mucous cell hyperplasia, and hypersecretion is also observed. Abundance of Asp f 13 from Asp. fumigatus highly correlates with the severity of asthma, as it can penetrate the airway submucosa. Moreover, it was found that Asp f 13 can proteolytically disrupt ASM and ECM interactions by degrading collagen I and fibronectin [167]; the underlying mechanism associated with enhancement of G protein coupled receptor induced inositol 1,4,5-trisphosphate (InsP3) production. In addition, a small concentration of Asp f 13 (0.001 μg·mL−1) can cause calcium mobilisation in ASM cells, which contributes to airway bronchoconstriction, while Asp f 13 (3 μg·mL−1) can promote ASM cell detachment and elongation in a protease-dependent manner.

Asp f 13 may also directly interact with the ASM layer as a result of epithelial barrier disruption, which prompts airway hyperresponsiveness (AHR) and remodelling [168, 169]. In addition, mice sensitised with active Epi p 1, from the Epicoccum purpurascens dust mite species, showed elevation of Epi p 1-specific IgE and IgG in serum, higher levels of IL-4 and IL-13 in BALF, as well as goblet cell metaplasia, increased mucus production, enhanced leucocyte infiltration and airway narrowing, compared to the inactive Epi p 1 group [79].

Signalling pathways involved in mediating the allergen serine protease-induced response

PARs

Expression and activation of PARs in the airways

PARs are the major G-coupled protein receptor involved in allergen serine protease-mediated allergic airway diseases. The PAR family consists of four subtypes including PAR-1, -2, -3 and -4 [170]. It has been reported that the PARs are expressed in epithelial, endothelial and smooth muscle cells, while PARs 1–3 are also expressed in fibroblasts. In immune cells, PAR-1 and -2 are expressed on mast cells, eosinophils, neutrophils, monocytes, macrophages, T- and B-cells, and DCs, while to date, PAR-3 expression has only been discovered in mast cells, eosinophils, monocytes, macrophages and DCs. Expression of PAR-4 is found on mast cells, monocytes, macrophages and T-cells [171]. Among these four subtypes, PAR-1, -3 and -4 can be activated by thrombin and PAR-2 by TLP and CTLP activities. Canonical protease activation of PARs is achieved by irreversible cleavage of the extracellular N-terminus, which exposes a new N-terminal peptide that acts as a tethered ligand to activate the transmembrane receptor domain, triggering G-protein and β-arrestin activation [170]. PARs regulate several cellular responses by mediating conversion of G-proteins from guanosine diphosphate to guanosine triphosphate (GTP), resulting in dissociation of GTP-bound activated Gα from Gβ/γ subunits and can activate multiple second messenger signalling cascades such as Ca2+, cAMP and diacyl glycerol [170].

Activation of PARs by allergen serine proteases

Activation of PARs by allergen serine proteases is involved in the regulation of MCC in the epithelial barrier, Th2 cell polarisation as well as ASM cell contraction. Figure 4 and table 2 further summarise the role of PARs in allergen serine protease-associated inflammation in allergic airway diseases. Based on these studies, it can be concluded that activation of PARs by allergen serine proteases leads to a pro-inflammatory immune response by promoting the release of alarmins such as IL-33 and TSLP, induction of cytokines, and chemokine expression such as IL-8, IL-6, GM-CSF, IL-1β and CCL20, as well as immune cell recruitment. Simultaneously, PAR activation by allergen proteases also increases total IgE levels and promotes Th2 polarisation. In addition, elevation of intracellular calcium by activation of PARs contributes to constriction of ASM and an increased secretion of pro-inflammatory mediators by airway epithelial cells. Of note, PAR-2 expression is elevated in asthmatic airway epithelial cells and correlates with asthma severity [188]. Moreover, increased expression of PAR-2 has been observed in monocytes derived from patients with AR or asthma, thereby contributing to TNF-α expression. Asthma and healthy hPBECs grown at the ALI also show different Ca2+ signalling in response to stimulation by HDM with the apical response of asthma airway cells thought to involve signalling via PAR-2, PAR-4 and TRPV1, transient receptor potential ankyrin 1 and TRPV4; the antagonist of these channels only had a small impact on basolateral HDM-induced Ca2+ response [137]. It is also possible that other transient receptor potential channels such as TRPV2 (localised on the basolateral side) may play a role in the regulation of basolateral HDM-induced Ca2+ mobilisation, thus further study is required.

FIGURE 4
FIGURE 4

The allergen serine protease-induced response can be mediated via activation of protease-activated receptor (PAR) signalling. Allergen serine proteases, such as those derived from house dust mites, have both allergenic and proteolytic activities that can stimulate the generation of the alarmins, interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) from airway epithelial cells, leading to type 2 inflammation and an increase in IL-13 and IL-4. They can enter the submucosal area by cleaving junctional structures in the epithelium and compete with endogenous enzymes to irreversibly cleave the extracellular amino terminus of PARs. The newly generated N-terminus then acts as a tethered ligand (TL) to activate the receptor. This induces an increase in the concentration of intracellular calcium, via intracellular G-protein and arrestin signalling, which drives increases in the expressions of various pro-inflammatory cytokines (e.g. IL-8, IL-6, granulocyte macrophage–colony-stimulating factor (GM-CSF), IL-1β and chemokine ligand 20 (CCL20)). All the effects caused by allergen proteases may disrupt the anti-protease and protease balance and can cause airways smooth muscle constriction and airway remodelling. Figure created with BioRender.com.

View this table:
TABLE 2

Protease-activated receptors (PARs) involved in an allergen serine protease-induced inflammatory response

According to table 2, PAR-2 is the primary PAR involved in allergen serine protease-induced signalling of allergic inflammatory responses. It has also been discovered that the T2 environment-derived cytokine response alters PAR-2 polarisation in human airway epithelial cells, therefore reducing tolerance to protease exposure and resulting in the promotion of allergic inflammation in the airway [157]. Even though it was initially suggested that G protein-coupled receptors function as solitary monomeric units, there is evidence that PARs can form dimers or can transactivate other types of receptors [189]. PAR-2 facilitates ROS signalling and has potential to transactivate receptor tyrosine kinases (RTKs) in the airways [190]. PAR-1 can induce activation of a disintegrin and metalloproteinase (ADAM) 17, which allows further cleavage of epidermal growth factor receptor (EGFR) and downstream RTK activation [191].

PRRs

PRRs and the complement system

The presence of PRRs on the surface of cells helps the immune system identify environmental potentially pathogenic substances such as bacteria and viruses and includes Toll-like receptors (TLRs) as well as C-type lectin receptors (CLRs) [192]. These transmembrane sensors activate components of the complement system (Cx-proteins), which are vital parts of the innate immune response. This complementarily involves a cascade of protease-mediated reactions leading to the activation and amplification of an inflammatory response, as well as opsonisation or the direct killing of pathogens and targeted cells by lysis.

Activation of TLRs by allergen serine proteases

TLR4 is the primary TLR associated with allergen serine protease-induced responses in airway epithelium. Activation of TLRs requires involvement of CD14 and myeloid differentiation factor-2, followed by downstream activation of Toll–interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP) or the Toll/IL-1R resistance TRIF-related adaptor molecule (TRAM). The TIRAP-activated myeloid differentiation primary response gene 88 (MyD88) results in activation of transcription factor NF-κB and contributes to inflammatory responses, leading to elevated ROS aggregation. Downstream of TRAM includes regulation of type 1 interferon associated signalling [193]. Moreover, TLR4 is also involved in the co-ordinated modulation of EGFR signalling, which then initiates activation of pannexons (a channel that can release ATP). This, in turn, induces ADAM10 and purinoceptor activation, triggering IgE-independent cytokine production [113].

An agonist of TLR4 is fibrinogen cleavage products (FCPs), which can be generated either by direct degradation of fibrinogen by allergen serine proteases or in concert with native thrombin that can also be dysregulated by allergen proteolysis. Immunoreactive FCPs, generated by allergen serine proteases from Asp. species (Asp. melleus, Asp. niger) and also dust mite species (Dermatophagoides (Der.) farina, Der. pteronyssinus, Tyrophagus putrescentiae), are distinguished by fibrinogen α chain deficiency and preserved fibrinogen β and γ chains, which promotes subsequent allergic airway inflammation by high-affinity binding with TLR4 [194, 195].

Activation of CLRs by allergen serine proteases

Allergen serine proteases trigger CLRs that are expressed in cells resident in the airways including subsets of DCs, macrophage, monocytes, basophils and epithelial cells. For example, dectin-1 from the CLR family can recognise allergens derived from fungi and HDMs and promotes plasmacytoid DC-mediated Th2 polarisation from naive T-cells [192]. Cleavage and inactivation of the hDectin-1 isoform by serine proteases from Asp. fumigatus may, therefore, impair the ability of the complement system to clear Asp. fumigatus from the lung, thus contributing to airway exacerbation in patients [196]. Normally, C3, C4 and C5 proteins are degraded by endogenous proteases to generate C3a, C3b, C4a, C4b, C5a and C5b, respectively. However, increased exposure to allergen serine proteases may lead to excessive degradation of these activated components which can dysregulate the complement cascade thus affecting the efficiency and effectiveness of the immune response [197]. For instance, C5-deficient mice develop AHR and pulmonary inflammation and C3a plays an essential role in ILC2-regulated Th2-allergic airway diseases [197]. Mice lacking C3aR and challenged with Asp. or HDM showed diminished Th2 inflammation coupled with reduced AHR, IgE production, eosinophilic inflammation as well as mucus production compared to wild-type mice [198, 199].

Synergetic effects of other stimuli and allergen serine proteases

Urbanisation and socioeconomic development have driven heightened energy consumption and waste discharge, thereby increasing the risk of exposure to air pollution and chemical hazards [200]. Such chemical insults, including the effects of cigarette smoke, can augment disruption of airway epithelial barriers by allergen proteases which facilitate access of allergens to antigen-presenting cells, with subsequent allergic sensitisation [201]. The synergistic effect of rhinovirus and HDMs (serine and cysteine protease activities) contributes to the shedding of C-X3-C motif chemokine ligand 1 during allergen exposure and virus infection, thereby promoting airway remodelling and asthma exacerbations [202]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by first binding to angiotensin-converting enzyme 2 (ACE2), a membrane protein that has an enzymatic domain located on the outer surface of various human cells, followed by priming of the spike protein by transmembrane protease serine 2 (TMPRSS2) [203]. A higher expression of TMPRSS2 in asthma was observed by analysis of various RNA-seq databases, which highlighted the possibility that the cleavage of the SARS-CoV-2 spike protein might be more efficient in asthmatic airways [204]. An increased expression of TMPRSS2 that was positively associated with type 2 cytokines was also found in both nasal and epithelial cells in type 2 asthma, although the inverse was observed for ACE2 [205]. Downregulation of ACE2 in both the epithelium and submucosa of endobronchial biopsies from patients with allergic asthma 24 h after allergen inhalation challenge has since been observed [206]. Based on the perceived conflict between TMPRSS2 and ACE2 results, further research to study the role of allergen and allergen proteases in virus infection susceptibility is therefore required. Detergents, ozone, particulate matter (PM)2.5, PM10 and diesel fumes have reported to impair epithelial barrier permeability [200]. In addition, nanoparticles and micro/nanoplastics have been demonstrated to change hPBEC metabolism and increase ROS [9]. However, synergetic effects with allergen proteases remain unclear.

Inhibition of allergen serine proteases as a therapeutic strategy

The development of protease inhibitors is a well-established drug development strategy to combat dysregulated protease activities associated with disease. Within the airways, inhibitors of NE (e.g. recombinant AAT) and the neutrophil serine protease activator, dipeptidyl peptidase I/cathepsin C (e.g. brensocatib) offer opportunities to aid the management of chronic airways diseases such as bronchiectasis, CF and COPD [207, 208].

The protease–antiprotease imbalance in airway disease

Allergen serine proteases contribute to the development of allergic airways disease through their ability to impair the epithelial barrier, stimulate and disrupt elements of the immune system, as well as directing tissue injury. In healthy airways, excessive tissue damage caused by exogenous proteases as well as dysregulated host proteases (such as neutrophil serine proteases and MMPs) is prevented by the presence of several endogenous protease inhibitors that can neutralise aberrant proteolytic activities. However, in chronic airway diseases, including allergic conditions, a protease–antiprotease imbalance prevails due to a dysregulation of protease expression and activation coupled with a disruption of the natural protease inhibitor defences [209]. In asthma, increased tryptase and elastase secretion from mast cells in a T2 environment further contribute to airway remodelling [210] and in BALB/c mice sensitised and challenged (primary) with ovalbumin, NE was shown to contribute to the development of both allergic airway inflammation and AHR [211]. In contrast, the expression of the serine protease inhibitor Kazal-type 5, which is responsible for maintaining epithelia barrier integrity and function, is downregulated in both noneosinophilic and eosinophilic CRS [212]. Genetic risk factors for asthma and COPD include AAT deficiency (AATD) [213]. Exogenous allergen proteases also add to the protease burden in the airways. Damage to intracellular junctions and an increase in barrier permeability exacerbates the host response and may contribute to elevated levels of oxidative stress and airway epithelial cell senescence, leading to a downstream inflammatory storm [214]. A protease–antiprotease imbalance can, therefore, contribute directly to the progression of chronic inflammation in the airways, lung tissue damage and AHR in asthma.

Augmentation of endogenous protease inhibitors

Endogenous protease inhibitor intravenous augmentation therapy has been solely licensed for AATD-associated emphysema. Other potential strategies to rectify AAT deficiency include the use of CRISPR (clustered regularly interspaced short palindromic repeats), stem-cell technologies or the introduction of replacement hepatocytes [215]. These approaches, however, need thorough evaluation and safety profiling before any first-in-man studies can be considered. Moreover, it remains controversial to suggest AAT augmentation therapy for asthma even though, conversely, individuals with AATD often demonstrate an increased prevalence of asthma [216]. Indeed, studies have shown AAT augmentation to not be any more efficacious in AATD individuals with asthma compared to those without; therefore, there is no evidence to indicate any significant impact of AAT augmentation on respiratory symptoms or exacerbations in asthma [216].

In addition to AAT (SERPINA1), other members of the serpin (SERine Protease INhibitor) superfamily have been implicated in the development of allergic asthma [217]. SERPINB3 and SERPINB4 are thought to be associated with the maintenance of allergic memory Th2 cells [218]. Inhibition of SERPINB10 can significantly ameliorate HDM-induced Th2 cytokine secretion and levels of HDM-specific IgE [219]. SERPINE1 gene polymorphisms are strongly implicated in the pathological tissue remodelling processes of CRS without nasal polyps and are associated with an increased risk of allergic disease, which indicates a reduction of SERPINE1 may assist improvement of CRS symptoms and asthma [220]. Inhibition of SERPINE2 can downregulate MMP-9 and tissue inhibitors of metalloproteinases-1 expression in asthmatic mice [221]. Due to the complex and varied roles played by endogenous protease inhibitors in allergic airway disease, further research targeting the serpin superfamily will be required to assess their potential as therapeutic targets.

Broad spectrum serine protease inhibitors in the treatment of allergic airway diseases and potential off-target effects

The use of broad-spectrum protease inhibitors in a variety of allergen models is summarised in table 3. These studies and others suggest protease inhibition as an attractive therapeutic strategy to combat the excessive protease burden inflicted by both exogenous allergen and endogenous host proteases in chronic and allergic airways diseases. Although broad spectrum, small-molecule serine protease inhibitors such as nafamostat mesylate offer promise; they can promote widespread immune suppression and some cytokine activation, e.g. upregulation of IL-12 and IL-10 in alveolar macrophages [229]. This highlights the potential off-target effects associated with nonselective broad-spectrum serine protease inhibition. Moreover, a case study suggested that high concentration of gabexate mesylate may lead to blood vessel damage and allergic response [231]. Thus, the use of selective protease inhibitors may offer a preferential alternative.

View this table:
TABLE 3

Examples of treatment of airway-associated serine proteases by protease inhibitors

Selective inhibition of allergen serine proteases

An inherent difficulty in the development of selective inhibitors of the allergen serine proteases is that exogenous serine proteases and endogenous proteases share similar active sites and specificities even though they may have different structure. For instance, the German cockroach TLPs contain six conserved cysteines that are also found in human trypsins, but two conserved cysteines found in mammalian trypsins are absent in the cockroach enzymes [93]. Our group reported that a Bowman–Birk proteinase inhibitor (BBI)-type peptide isolated from skin secretions of the amphibian Pelophylax esculentus (PE) named PE-BBI [232], can selectively protect airway epithelial barrier function by directly inhibiting TLP activities in whole-body German cockroach extract (CRE), but had no effect on host protease activities [222, 225]. The highly selective inhibition of allergen TLPs by PE-BBI also extends to HDM proteases where PE-BBI reduced HDM-induced Ca2+ mobilisation in submerged cultures of asthma hPBECs, but did not affect subsequent Ca2+ mobilisation induced by trypsin [137]. We also synthesised a series of peptide derivatives containing an N-alkyl glycine analogue of arginine. Among these compounds, an irreversible trypsin-like protease inhibitor NAP858 showed good inhibitory effect against CRE activities [233].

Conclusions

Airborne serine protease allergens are a significant risk factor for the initiation and progression of allergic airways disease such as allergic asthma, AR and CSR. Degradation of TJs and ECM components leads to airway remodelling, while penetration of allergens through breeches in the epithelial barrier and contact with immune cells and components leads to an excessive pro-inflammatory environment and dysregulation of the protease–antiprotease balance. Selective inhibition of allergen serine proteases by inhibitors, such as PE-BBI, offers a potential strategy to reduce AHR, airway inflammation as well as airway constriction in allergic airways disease.

Key messages

  • Common airborne indoor allergens contain damaging serine protease activities.

  • Allergen serine proteases are implicated in epithelial barrier dysfunction and promotion of allergic inflammation and sensitisation.

  • Selective inhibition of allergen proteases may dampen AHR, inflammation and constriction in allergic airways disease.

Questions for future research

  • Does selective protease inhibition of allergen proteases by compounds such as PE-BBI and NAP858 protect the airways and suppress immune responses in relevant in vivo allergen challenge models?

  • Although long-term inhaled protease inhibitor therapy targeting allergen proteases may not be clinically viable, could a spray formulation be developed to suppress allergen protease activity within indoor environments, particularly those deemed to be risky for someone living with allergic asthma?

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Author contributions: The review was conceived by X. Ouyang and S.L. Martin who were also responsible for preparing the first draft of the manuscript. All authors provided critical feedback and contributed to the final version of the manuscript.

  • Conflict of interest: All authors have nothing to disclose.

  • Support statement: X. Ouyang is supported by a studentship from the China Scholarship Council. J.A. Reihill is funded via an MRC Innovation Scholar Award (grant reference MR/W004135/1). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received June 22, 2023.
  • Accepted February 28, 2024.
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References

  1. ↵
    1. Kuan-Hsiang GH,
    2. Chen Hsuan ST
    1. Vujnovic S,
    2. Domuz A
    . Epidemiological aspects of rhinitis and asthma: comorbidity or united airway disease. In: Kuan-Hsiang GH, Chen Hsuan ST, eds. Asthma Diagnosis and Management. Rijeka, IntechOpen, 2018; Ch. 2.
  2. ↵
    1. Vos T,
    2. Lim SS,
    3. Abbafati C, et al.
    Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020; 396: 1204–1222. doi:10.1016/S0140-6736(20)30925-9
    OpenUrlCrossRefPubMed
  3. ↵
    1. Nur Husna SM,
    2. Tan H-TT,
    3. Md Shukri N, et al.
    Allergic rhinitis: a clinical and pathophysiological overview. Front Med 2022; 9: 874114. doi:10.3389/fmed.2022.874114
    OpenUrl
  4. ↵
    1. Albu S
    . Chronic rhinosinusitis–an update on epidemiology, pathogenesis and management. J Clin Med 2020; 9: 2285. doi:10.3390/jcm9072285
    OpenUrl
  5. ↵
    1. Sunman B,
    2. Ademhan Tural D,
    3. Ozsezen B, et al.
    Current approach in the diagnosis and management of allergic bronchopulmonary aspergillosis in children with cystic fibrosis. Front Pediatr 2020; 8: 582964. doi:10.3389/fped.2020.582964
    OpenUrl
  6. ↵
    1. Marseglia GL,
    2. Caimmi S,
    3. Marseglia A, et al.
    Rhinosinusitis and asthma. Int J Immunopathol Pharmacol 2010; 23: Suppl. 1, 29–31. doi:10.1177/03946320100230S108
    OpenUrlPubMed
  7. ↵
    1. Tajiri T,
    2. Niimi A,
    3. Matsumoto H, et al.
    Prevalence and clinical relevance of allergic rhinitis in patients with classic asthma and cough variant asthma. Respiration 2014; 87: 211–218. doi:10.1159/000355706
    OpenUrlCrossRef
  8. ↵
    1. Rosado Ingelmo A,
    2. Doña Diaz I,
    3. Cabañas Moreno R, et al.
    Clinical practice guidelines for diagnosis and management of hypersensitivity reactions to contrast media. J Investig Allergol Clin Immunol 2016; 26: 144–155. doi:10.18176/jiaci.0058
    OpenUrl
  9. ↵
    1. Sozener Z C,
    2. Cevhertas L,
    3. Nadeau K, et al.
    Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol 2020; 145: 1517–1528. doi:10.1016/j.jaci.2020.04.024
    OpenUrl
  10. ↵
    1. Hedstrom L
    . Serine protease mechanism and specificity. Chem Rev 2002; 102: 4501–4524. doi:10.1021/cr000033x
    OpenUrlCrossRefPubMed
  11. ↵
    1. World Health Organization and International Union of Immunological Societies Allergen Nomenclature Sub-Committee
    . Allergen nomenclature. Date last accessed: 30 May 2023. Date last updated: 7 December 2022. https://allergen.org
    1. Gabriel MF,
    2. Postigo I,
    3. Gutiérrez-Rodríguez A, et al.
    Alt a 15 is a new cross-reactive minor allergen of Alternaria alternata. Immunobiology 2016; 221: 153–160. doi:10.1016/j.imbio.2015.09.014
    OpenUrl
    1. Lee BR,
    2. Furukawa M,
    3. Yamashita K, et al.
    Aorsin, a novel serine proteinase with trypsin-like specificity at acidic pH. Biochem J 2003; 371: 541–548. doi:10.1042/bj20021691
    OpenUrlAbstract/FREE Full Text
    1. Kolattukudy PE,
    2. Lee JD,
    3. Rogers LM, et al.
    Evidence for possible involvement of an elastolytic serine protease in aspergillosis. Infect Immun 1993; 61: 2357–2368. doi:10.1128/iai.61.6.2357-2368.1993
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Chow LP,
    2. Liu SL,
    3. Yu CJ, et al.
    Identification and expression of an allergen Asp f 13 from Aspergillus fumigatus and epitope mapping using human IgE antibodies and rabbit polyclonal antibodies. Biochem J 2000; 346: 423–431. doi:10.1042/bj3460423
    OpenUrlAbstract/FREE Full Text
    1. Gautam P,
    2. Sundaram CS,
    3. Madan T, et al.
    Identification of novel allergens of Aspergillus fumigatus using immunoproteomics approach. Clin Exp Allergy 2007; 37: 1239–1249. doi:10.1111/j.1365-2222.2007.02765.x
    OpenUrlCrossRefPubMed
    1. Shen HD,
    2. Tam MF,
    3. Tang RB, et al.
    Aspergillus and Penicillium allergens: focus on proteases. Curr Allergy Asthma Rep 2007; 7: 351–356. doi:10.1007/s11882-007-0053-8
    OpenUrlCrossRefPubMed
    1. Shen HD,
    2. Lin WL,
    3. Tam MF, et al.
    Identification of vacuolar serine proteinase as a major allergen of Aspergillus fumigatus by immunoblotting and N-terminal amino acid sequence analysis. Clin Exp Allergy 2001; 31: 295–302. doi:10.1046/j.1365-2222.2001.01026.x
    OpenUrlCrossRefPubMed
    1. Abad A,
    2. Fernández-Molina JV,
    3. Bikandi J, et al.
    What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Rev Iberoam Micol 2010; 27: 155–182. doi:10.1016/j.riam.2010.10.003
    OpenUrlCrossRefPubMed
    1. Chou H,
    2. Lin WL,
    3. Tam MF, et al.
    Alkaline serine proteinase is a major allergen of Aspergillus flavus, a prevalent airborne Aspergillus species in the Taipei area. Int Arch Allergy Immunol 1999; 119: 282–290. doi:10.1159/000024205
    OpenUrlCrossRefPubMed
    1. Yu CJ,
    2. Chiou SH,
    3. Lai WY, et al.
    Characterization of a novel allergen, a major IgE-binding protein from Aspergillus flavus, as an alkaline serine protease. Biochem Biophys Res Commun 1999; 261: 669–675. doi:10.1006/bbrc.1999.1093
    OpenUrlCrossRefPubMed
    1. Frederick GD,
    2. Rombouts P,
    3. Buxton FP
    . Cloning and characterisation of pepC, a gene encoding a serine protease from Aspergillus niger. Gene 1993; 125: 57–64. doi:10.1016/0378-1119(93)90745-O
    OpenUrlCrossRefPubMed
  23. ↵
    1. Dong Z,
    2. Yang S,
    3. Lee BH
    . Bioinformatic mapping of a more precise Aspergillus niger degradome. Sci Rep 2021; 11: 693. doi:10.1038/s41598-020-80028-3
    OpenUrlCrossRef
    1. Shen HD,
    2. Han SH
    . Characterization of allergens of Penicillium and Aspergillus species. J Microbiol Immunol Infect 1998; 31: 141–145.
    OpenUrlPubMed
    1. Shen HD,
    2. Lin WL,
    3. Tam MF, et al.
    Alkaline serine proteinase: a major allergen of Aspergillus oryzae and its cross-reactivity with Penicillium citrinum. Int Arch Allergy Immunol 1998; 116: 29–35. doi:10.1159/000023921
    OpenUrlCrossRefPubMed
    1. Shi C,
    2. Miller JD
    . Characterization of the 41 kDa allergen Asp v 13, a subtilisin-like serine protease from Aspergillus versicolor. Mol Immunol 2011; 48: 1827–1834. doi:10.1016/j.molimm.2011.05.010
    OpenUrlCrossRefPubMed
    1. Shi C,
    2. Belisle D,
    3. Miller JD
    . Quantification of the Aspergillus versicolor allergen in house dust. J Immunol Methods 2011; 372: 89–94. doi:10.1016/j.jim.2011.06.034
    OpenUrlCrossRefPubMed
    1. Cheong N,
    2. Yang L,
    3. Lee BW, et al.
    Cloning of a group 3 allergen from Blomia tropicalis mites. Allergy 2003; 58: 352–356. doi:10.1034/j.1398-9995.2003.00033.x
    OpenUrlCrossRefPubMed
    1. Yang L,
    2. Cheong N,
    3. Wang DY, et al.
    Generation of monoclonal antibodies against Blo t 3 using DNA immunization with in vivo electroporation. Clin Exp Allergy 2003; 33: 663–668. doi:10.1046/j.1365-2222.2003.01648.x
    OpenUrlPubMed
    1. Chua KY,
    2. Cheong N,
    3. Kuo IC, et al
    . The Blomia tropicalis allergens. Protein Pept Lett 2007; 14: 325–333. doi:10.2174/092986607780363862.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Schoos AM,
    2. Chawes BL,
    3. Bloch J, et al.
    Children monosensitized to can f 5 show different reactions to male and female dog allergen extract provocation: a randomized controlled trial. J Allergy Clin Immunol Pract 2020; 8: 1592–7.e2. doi:10.1016/j.jaip.2019.12.012
    OpenUrl
    1. Mattsson L,
    2. Lundgren T,
    3. Everberg H, et al.
    Prostatic kallikrein: a new major dog allergen. J Allergy Clin Immunol 2009; 123: 362–368. doi:10.1016/j.jaci.2008.11.021
    OpenUrlPubMed
    1. Liccardi G,
    2. Calzetta L,
    3. Milanese M, et al.
    Can f 5 as a suitable marker of dog allergy: assess male dog exposure before banning it. J Allergy Clin Immunol 2019; 143: 1657–1658. doi:10.1016/j.jaci.2018.12.1007
    OpenUrl
    1. Villalta D,
    2. Milanese M,
    3. Da Re M, et al.
    Frequency of allergic sensitization to Can f 5 in north east Italy. An analysis of 1403 ISACs 112 (component resolved diagnosis) collected retrospectively. Eur Ann Allergy Clin Immunol 2019; 51: 186–189. doi:10.23822/EurAnnACI.1764-1489.89
    OpenUrl
    1. Sterner T,
    2. Uldahl A,
    3. Svensson Å, et al.
    IgE sensitization in a cohort of adolescents in southern Sweden and its relation to allergic symptoms. Clin Mol Allergy 2019; 17: 6. doi:10.1186/s12948-019-0110-6
    OpenUrl
    1. Vachová M,
    2. Panzner P,
    3. Vlas T, et al.
    Analysis of sensitization profiles in central European allergy patients focused on animal allergen molecules. Int Arch Allergy Immunol 2020; 181: 278–284. doi:10.1159/000505518
    OpenUrl
    1. Sánchez A,
    2. Cardona R,
    3. Munera M, et al.
    Nasal provocation test with cat and dog extracts: results according to molecular components. Pulm Med 2020; 2020: 6365314. doi:10.1155/2020/6365314
    OpenUrl
    1. Liccardi G,
    2. Calzetta L,
    3. Bilò MB, et al.
    A prevalent exposure to male dog is a risk factor for exclusive allergic sensitization to Can f 5: an Italian multicenter study. J Allergy Clin Immunol Pract 2020; 8: 2399–2401. doi:10.1016/j.jaip.2020.02.041
    OpenUrl
    1. Hemmer W,
    2. Sestak-Greinecker G,
    3. Braunsteiner T, et al.
    Molecular sensitization patterns in animal allergy: relationship with clinical relevance and pet ownership. Allergy 2021; 76: 3687–3696. doi:10.1111/all.14885
    OpenUrl
    1. Chou H,
    2. Tam MF,
    3. Lee LH, et al.
    Vacuolar serine protease is a major allergen of Cladosporium cladosporioides. Int Arch Allergy Immunol 2008; 146: 277–286. doi:10.1159/000121462
    OpenUrlCrossRefPubMed
    1. Pöll V,
    2. Denk U,
    3. Shen HD, et al.
    The vacuolar serine protease, a cross-reactive allergen from Cladosporium herbarum. Mol Immunol 2009; 46: 1360–1373. doi:10.1016/j.molimm.2008.11.017
    OpenUrlCrossRefPubMed
    1. Gupta R,
    2. Sharma V,
    3. Sridhara S, et al.
    Identification of serine protease as a major allergen of Curvularia lunata. Allergy 2004; 59: 421–427. doi:10.1046/j.1398-9995.2003.00378.x
    OpenUrlCrossRefPubMed
    1. Tripathi P,
    2. Nair S,
    3. Singh BP, et al.
    Molecular and immunological characterization of subtilisin like serine protease, a major allergen of Curvularia lunata. Immunobiology 2011; 216: 402–408. doi:10.1016/j.imbio.2010.06.009
    OpenUrl
    1. Ando T,
    2. Homma R,
    3. Ino Y, et al.
    Trypsin-like protease of mites: purification and characterization of trypsin-like protease from mite faecal extract Dermatophagoides farinae. Relationship between trypsin-like protease and Der f III. Clin Exp Allergy 1993; 23: 777–784. doi:10.1111/j.1365-2222.1993.tb00366.x
    OpenUrlCrossRefPubMed
    1. Smith WA,
    2. Thomas WR
    . Comparative analysis of the genes encoding group 3 allergens from Dermatophagoides pteronyssinus and Dermatophagoides farinae. Int Arch Allergy Immunol 1996; 109: 133–140. doi:10.1159/000237212
    OpenUrlPubMed
    1. Zhan ZK,
    2. Ji KM,
    3. Liu XY, et al.
    Monoclonal antibodies against recombinant Der f 3 reveal localization of Der f 3 in the gut and faecal pellets of Dermatophagoides farinae. Exp Appl Acarol 2010; 52: 63–71. doi:10.1007/s10493-010-9349-9
    OpenUrlPubMed
    1. Li N,
    2. Li CP,
    3. Diao JD, et al.
    Prediction and identification of linear B-cell epitopes in major group 3 allergen derived from Dermatophagoides farina. Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2014; 26: 296–299.
    OpenUrl
    1. Zhan X,
    2. Li C,
    3. Jiang Y, et al.
    Epitope-based vaccine for the treatment of Der f 3 allergy. Nutr Hosp 2015; 32: 2763–2770. doi:10.3305/nh.2015.32.6.9878
    OpenUrlCrossRef
    1. Teng F,
    2. Yu L,
    3. Bian Y, et al.
    In silico structural analysis of group 3, 6 and 9 allergens from Dermatophagoides farinae. Mol Med Rep 2015; 11: 3559–3564. doi:10.3892/mmr.2015.3166
    OpenUrl
    1. Erban T,
    2. Harant K,
    3. Hubert J
    . Detailed two-dimensional gel proteomic mapping of the feces of the house dust mite Dermatophagoides pteronyssinus and comparison with D. farinae: reduced trypsin protease content in D. pteronyssinus and different isoforms. J Proteomics 2017; 162: 11–19. doi:10.1016/j.jprot.2017.04.021
    OpenUrlPubMed
    1. Li B,
    2. Zou Z,
    3. Meng F, et al.
    Dust mite-derived Der f 3 activates a pro-inflammatory program in airway epithelial cells via PAR-1 and PAR-2. Mol Immunol 2019; 109: 1–11. doi:10.1016/j.molimm.2019.02.018
    OpenUrl
    1. Yasueda H,
    2. Mita H,
    3. Akiyama K, et al.
    Allergens from Dermatophagoides mites with chymotryptic activity. Clin Exp Allergy 1993; 23: 384–390. doi:10.1111/j.1365-2222.1993.tb00343.x
    OpenUrlCrossRefPubMed
    1. Kawamoto S,
    2. Mizuguchi Y,
    3. Morimoto K, et al.
    Cloning and expression of Der f 6, a serine protease allergen from the house dust mite, Dermatophagoides farinae. Biochim Biophys Acta 1999; 1454: 201–207. doi:10.1016/S0925-4439(99)00041-1
    OpenUrlPubMed
    1. Cui Y,
    2. Zhou Y,
    3. Shi W, et al.
    Molecular cloning, expression, sequence analyses of dust mite allergen Der f 6 and its IgE-binding reactivity with mite allergic asthma patients in southeast China. Mol Biol Rep 2012; 39: 961–968. doi:10.1007/s11033-011-0822-2
    OpenUrlCrossRefPubMed
    1. Jeong KY,
    2. Son M,
    3. Lee JH, et al.
    Allergenic characterization of a novel allergen, homologous to chymotrypsin, from German cockroach. Allergy Asthma Immunol Res 2015; 7: 283–289. doi:10.4168/aair.2015.7.3.283
    OpenUrl
  56. ↵
    1. Jeong KY,
    2. Lee JY,
    3. Son M, et al.
    Profiles of IgE sensitization to Der f 1, Der f 2, Der f 6, Der f 8, Der f 10, and Der f 20 in Korean house dust mite allergy patients. Allergy Asthma Immunol Res 2015; 7: 483–488. doi:10.4168/aair.2015.7.5.483
    OpenUrlPubMed
    1. Stewart GA,
    2. Ward LD,
    3. Simpson RJ, et al.
    The group III allergen from the house dust mite Dermatophagoides pteronyssinus is a trypsin-like enzyme. Immunology 1992; 75: 29–35.
    OpenUrlPubMed
    1. Bennett BJ,
    2. Thomas WR
    . Cloning and sequencing of the group 6 allergen of Dermatophagoides pteronyssinus. Clin Exp Allergy 1996; 26: 1150–1154. doi:10.1111/j.1365-2222.1996.tb00501.x
    OpenUrlCrossRefPubMed
    1. Smith WA,
    2. Thomas WR
    . Sequence polymorphisms of the Der p 3 house dust mite allergen. Clin Exp Allergy 1996; 26: 571–579. doi:10.1111/j.1365-2222.1996.tb00578.x
    OpenUrlCrossRefPubMed
    1. Maruo K,
    2. Akaike T,
    3. Ono T, et al.
    Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease. J Allergy Clin Immunol 1997; 100: 253–260. doi:10.1016/S0091-6749(97)70233-1
    OpenUrlCrossRefPubMed
    1. Sun G,
    2. Stacey MA,
    3. Schmidt M, et al.
    Interaction of mite allergens Der p3 and Der p9 with protease-activated receptor-2 expressed by lung epithelial cells. J Immunol 2001; 167: 1014–1021. doi:10.4049/jimmunol.167.2.1014
    OpenUrlAbstract/FREE Full Text
    1. Adam E,
    2. Hansen KK,
    3. Astudillo Fernandez O, et al.
    The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. J Biol Chem 2006; 281: 6910–6923. doi:10.1074/jbc.M507140200
    OpenUrlAbstract/FREE Full Text
    1. Hales BJ,
    2. Martin AC,
    3. Pearce LJ, et al.
    IgE and IgG anti-house dust mite specificities in allergic disease. J Allergy Clin Immunol 2006; 118: 361–367. doi:10.1016/j.jaci.2006.04.001
    OpenUrlCrossRefPubMed
    1. Kim N,
    2. Kwon SS,
    3. Lee J, et al.
    Protective effect of the DNA vaccine encoding the major house dust mite allergens on allergic inflammation in the murine model of house dust mite allergy. Clin Mol Allergy 2006; 4: 4. doi:10.1186/1476-7961-4-4
    OpenUrlPubMed
    1. Chapman MD,
    2. Wünschmann S,
    3. Pomés A
    . Proteases as Th2 adjuvants. Curr Allergy Asthma Rep 2007; 7: 363–367. doi:10.1007/s11882-007-0055-6
    OpenUrlCrossRefPubMed
  66. ↵
    1. Dumez ME,
    2. Teller N,
    3. Mercier F, et al.
    Activation mechanism of recombinant Der p 3 allergen zymogen: contribution of cysteine protease Der p 1 and effect of propeptide glycosylation. J Biol Chem 2008; 283: 30606–30617. doi:10.1074/jbc.M803041200
    OpenUrlAbstract/FREE Full Text
    1. Herman J,
    2. Thelen N,
    3. Smargiasso N, et al.
    Der p 1 is the primary activator of Der p 3, Der p 6 and Der p 9 the proteolytic allergens produced by the house dust mite Dermatophagoides pteronyssinus. Biochim Biophys Acta 2014; 1840: 1117–1124. doi:10.1016/j.bbagen.2013.11.017
    OpenUrl
    1. Bouaziz A,
    2. Walgraffe D,
    3. Bouillot C, et al.
    Development of recombinant stable house dust mite allergen Der p 3 molecules for component-resolved diagnosis and specific immunotherapy. Clin Exp Allergy 2015; 45: 823–834. doi:10.1111/cea.12452
    OpenUrlCrossRef
    1. Dumez ME,
    2. Herman J,
    3. Campisi V, et al.
    The proline-rich motif of the proDer p 3 allergen propeptide is crucial for protease-protease interaction. PloS One 2013; 8: e68014. doi:10.1371/journal.pone.0068014
    OpenUrl
    1. Takahashi K,
    2. Taniguchi M,
    3. Fukutomi Y, et al.
    Oral mite anaphylaxis caused by mite-contaminated okonomiyaki/pancake-mix in Japan: 8 case reports and a review of 28 reported cases. Allergol Int 2014; 63: 51–56. doi:10.2332/allergolint.13-OA-0575
    OpenUrl
    1. Jacquet A,
    2. Campisi V,
    3. Szpakowska M, et al.
    Profiling the extended cleavage specificity of the house dust mite protease allergens Der p 1, Der p 3 and Der p 6 for the prediction of new cell surface protein substrates. Int J Mol Sci 2017; 18: 1373. doi:10.3390/ijms18071373
    OpenUrl
    1. Randall TA,
    2. London RE,
    3. Fitzgerald MC, et al.
    Proteases of Dermatophagoides pteronyssinus. Int J Mol Sci 2017; 18: 1204. doi:10.3390/ijms18061204
    OpenUrl
    1. Huang Z,
    2. Zou X,
    3. Chen H, et al.
    Identifying potential co-sensitization and cross-reactivity patterns based on component-resolved diagnosis. Int Arch Allergy Immunol 2020; 181: 81–93. doi:10.1159/000504320
    OpenUrl
    1. Zou X,
    2. Hu H,
    3. Huang Z, et al.
    Serum levels of specific immunoglobulin E to Dermatophagoides pteronyssinus allergen components in patients with allergic rhinitis or/and asthma. Allergy Asthma Proc 2021; 42: e40–e46. doi:10.2500/aap.2021.42.200105
    OpenUrl
    1. King C,
    2. Simpson RJ,
    3. Moritz RL, et al.
    The isolation and characterization of a novel collagenolytic serine protease allergen (Der p 9) from the dust mite Dermatophagoides pteronyssinus. J Allergy Clin Immunol 1996; 98: 739–747. doi:10.1016/S0091-6749(96)70121-5
    OpenUrlCrossRefPubMed
    1. Bisht V,
    2. Arora N,
    3. Singh BP, et al.
    Epi p 1, an allergenic glycoprotein of Epicoccum purpurascens is a serine protease. FEMS Immunol Med Microbiol 2004; 42: 205–211. doi:10.1016/j.femsim.2004.05.003
    OpenUrlCrossRefPubMed
    1. Bisht V,
    2. Arora N,
    3. Singh BP, et al.
    Purification and characterization of a major cross-reactive allergen from Epicoccum purpurascens. Int Arch Allergy Immunol 2004; 133: 217–224. doi:10.1159/000076827
    OpenUrlCrossRefPubMed
    1. Kukreja N,
    2. Arora N,
    3. Singh BP, et al.
    Role of glycoproteins isolated from Epicoccum purpurascens in host–pathogen interaction. Pathobiology 2007; 74: 186–192. doi:10.1159/000103378
    OpenUrlPubMed
  79. ↵
    1. Kukreja N,
    2. Sridhara S,
    3. Singh BP, et al.
    Effect of proteolytic activity of Epicoccum purpurascens major allergen, Epi p 1 in allergic inflammation. Clin Exp Immunol 2008; 154: 162–171. doi:10.1111/j.1365-2249.2008.03762.x
    OpenUrlCrossRefPubMed
    1. Yeh CC,
    2. Tai HY,
    3. Chou H, et al.
    Vacuolar serine protease is a major allergen of Fusarium proliferatum and an IgE-cross reactive pan-fungal allergen. Allergy Asthma Immunol Res 2016; 8: 438–444. doi:10.4168/aair.2016.8.5.438
    OpenUrl
    1. Shen HD,
    2. Lin WL,
    3. Tsai JJ, et al.
    Allergenic components in three different species of Penicillium: crossreactivity among major allergens. Clin Exp Allergy 1996; 26: 444–451. doi:10.1111/j.1365-2222.1996.tb00561.x
    OpenUrlPubMed
    1. Shen HD,
    2. Lin WL,
    3. Liaw SF, et al.
    Characterization of the 33-kilodalton major allergen of Penicillium citrinum by using MoAbs and N-terminal amino acid sequencing. Clin Exp Allergy 1997; 27: 79–86. doi:10.1111/j.1365-2222.1997.tb00676.x
    OpenUrlPubMed
    1. Chou H,
    2. Lai HY,
    3. Tam MF, et al.
    cDNA cloning, biological and immunological characterization of the alkaline serine protease major allergen from Penicillium chrysogenum. Int Arch Allergy Immunol 2002; 127: 15–26. doi:10.1159/000048165
    OpenUrlCrossRefPubMed
    1. Chiu LL,
    2. Perng DW,
    3. Yu CH, et al.
    Mold allergen, pen C 13, induces IL-8 expression in human airway epithelial cells by activating protease-activated receptor 1 and 2. J Immunol 2007; 178: 5237–5244. doi:10.4049/jimmunol.178.8.5237
    OpenUrlAbstract/FREE Full Text
    1. Chen JC,
    2. Chiu LL,
    3. Lee KL, et al.
    Identification of critical amino acids in an immunodominant IgE epitope of Pen c 13, a major allergen from Penicillium citrinum. PloS One 2012; 7: e34627. doi:10.1371/journal.pone.0034627
    OpenUrlCrossRefPubMed
    1. Shen HD,
    2. Lin WL,
    3. Tam MF, et al.
    Characterization of allergens from Penicillium oxalicum and P. notatum by immunoblotting and N-terminal amino acid sequence analysis. Clin Exp Allergy 1999; 29: 642–651. doi:10.1046/j.1365-2222.1999.00509.x
    OpenUrlPubMed
    1. Chou H,
    2. Chang CY,
    3. Tsai JJ, et al.
    The prevalence of IgE antibody reactivity against the alkaline serine protease major allergen of Penicillium chrysogenum increases with the age of asthmatic patients. Ann Allergy Asthma Immunol 2003; 90: 248–253. doi:10.1016/S1081-1206(10)62150-3
    OpenUrlPubMed
    1. Lai HY,
    2. Tam MF,
    3. Chou H, et al.
    Molecular and structural analysis of immunoglobulin E-binding epitopes of Pen ch 13, an alkaline serine protease major allergen from Penicillium chrysogenum. Clin Exp Allergy 2004; 34: 1926–1933. doi:10.1111/j.1365-2222.2004.02115.x
    OpenUrlPubMed
  89. ↵
    1. Shen HD,
    2. Chou H,
    3. Tam MF, et al.
    Molecular and immunological characterization of Pen ch 18, the vacuolar serine protease major allergen of Penicillium chrysogenum. Allergy 2003; 58: 993–1002. doi:10.1034/j.1398-9995.2003.00107.x
    OpenUrlCrossRefPubMed
    1. Cheng TT,
    2. Tam MF,
    3. Chou H, et al.
    Lys89, Lys90, and Phe91 are critical core amino acid residues of the Pen ch 18 major fungal allergen recognized by human IgE antibodies. Biochem Biophys Res Commun 2008; 375: 671–674. doi:10.1016/j.bbrc.2008.08.097
    OpenUrlCrossRefPubMed
    1. Yu CJ,
    2. Chen YM,
    3. Su SN, et al.
    Molecular and immunological characterization and IgE epitope mapping of Pen n 18, a major allergen of Penicillium notatum. Biochem J 2002; 363: 707–715. doi:10.1042/bj3630707
    OpenUrlAbstract/FREE Full Text
    1. Shen HD,
    2. Wang CW,
    3. Lin WL, et al.
    cDNA cloning and immunologic characterization of Pen o 18, the vacuolar serine protease major allergen of Penicillium oxalicum. J Lab Clin Med 2001; 137: 115–124. doi:10.1067/mlc.2001.112096
    OpenUrlCrossRefPubMed
  93. ↵
    1. Polley DJ,
    2. Mihara K,
    3. Ramachandran R, et al.
    Cockroach allergen serine proteinases: isolation, sequencing and signalling via proteinase-activated receptor-2. Clin Exp Allergy 2017; 47: 946–960. doi:10.1111/cea.12921
    OpenUrl
    1. Sudha VT,
    2. Arora N,
    3. Gaur SN, et al.
    Identification of a serine protease as a major allergen (Per a 10) of Periplaneta americana. Allergy 2008; 63: 768–776. doi:10.1111/j.1398-9995.2007.01602.x
    OpenUrlCrossRefPubMed
    1. Chen H,
    2. Goldberg MS,
    3. Villeneuve PJ
    . A systematic review of the relation between long-term exposure to ambient air pollution and chronic diseases. Rev Environ Health 2008; 23: 243–297. doi:10.1515/reveh.2008.23.4.243
    OpenUrlPubMed
    1. Govindaraj D,
    2. Gaur SN,
    3. Arora N
    . Characterization of recombinant per a 10 from Periplaneta americana. Clin Vaccine Immunol 2013; 20: 262–268. doi:10.1128/CVI.00461-12
    OpenUrlAbstract/FREE Full Text
    1. Tamaki FK,
    2. Pimentel AC,
    3. Dias AB, et al.
    Physiology of digestion and the molecular characterization of the major digestive enzymes from Periplaneta americana. J Insect Physiol 2014; 70: 22–35. doi:10.1016/j.jinsphys.2014.08.007
    OpenUrlCrossRef
    1. Lee MF,
    2. Chen YH,
    3. Chiang CH, et al.
    Analysis of 10 environmental allergen components of the American cockroach in Taiwan. Ann Allergy Asthma Immunol 2016; 117: 535–41.e1. doi:10.1016/j.anai.2016.09.432
    OpenUrl
    1. Tong X,
    2. Guo M,
    3. Jin M, et al.
    In silico epitope prediction, expression and functional analysis of Per a 10 allergen from the American cockroach. Int J Mol Med 2016; 38: 1806–1814. doi:10.3892/ijmm.2016.2790
    OpenUrl
    1. Govindaraj D,
    2. Sharma S,
    3. Gaur SN, et al.
    Immunogenic peptides: B & T cell epitopes of Per a 10 allergen of Periplaneta americana. Mol Immunol 2016; 80: 24–32. doi:10.1016/j.molimm.2016.10.007
    OpenUrl
    1. Mattison CP,
    2. Khurana T,
    3. Tarver MR, et al.
    Cross-reaction between Formosan termite (Coptotermes formosanus) proteins and cockroach allergens. PloS One 2017; 12: e0182260. doi:10.1371/journal.pone.0182260
    OpenUrl
    1. Caraballo L,
    2. Valenta R,
    3. Puerta L, et al.
    The allergenic activity and clinical impact of individual IgE-antibody binding molecules from indoor allergen sources. World Allergy Organ J 2020; 13: 100118. doi:10.1016/j.waojou.2020.100118
    OpenUrl
    1. Chou H,
    2. Tam MF,
    3. Lee SS, et al.
    A vacuolar serine protease (Rho m 2) is a major allergen of Rhodotorula mucilaginosa and belongs to a class of highly conserved pan-fungal allergens. Int Arch Allergy Immunol 2005; 138: 134–141. doi:10.1159/000088435
    OpenUrlPubMed
    1. Beckham SA,
    2. Boyd SE,
    3. Reynolds S, et al.
    Characterization of a serine protease homologous to house dust mite group 3 allergens from the scabies mite Sarcoptes scabiei. J Biol Chem 2009; 284: 34413–34422. doi:10.1074/jbc.M109.061911
    OpenUrlAbstract/FREE Full Text
    1. Woodfolk JA,
    2. Wheatley LM,
    3. Piyasena RV, et al.
    Trichophyton antigens associated with IgE antibodies and delayed type hypersensitivity. Sequence homology to two families of serine proteinases. J Biol Chem 1998; 273: 29489–29496. doi:10.1074/jbc.273.45.29489
    OpenUrlAbstract/FREE Full Text
    1. Woodfolk JA
    . Allergy and dermatophytes. Clin Microbiol Rev 2005; 18: 30–43. doi:10.1128/CMR.18.1.30-43.2005
    OpenUrlAbstract/FREE Full Text
    1. Liao EC,
    2. Hsu EL,
    3. Tsai JJ, et al.
    Immunologic characterization and allergenicity of recombinant Tyr p 3 allergen from the storage mite Tyrophagus putrescentiae. Int Arch Allergy Immunol 2009; 150: 15–24. doi:10.1159/000210376
    OpenUrlCrossRefPubMed
    1. Liao EC,
    2. Ho CM,
    3. Tsai JJ
    . Prevalence of Tyrophagus putrescentiae hypersensitivity in subjects over 70 years of age in a veterans’ nursing home in Taiwan. Int Arch Allergy Immunol 2010; 152: 368–377. doi:10.1159/000288290
    OpenUrlPubMed
    1. Yu CH,
    2. Tsai JJ,
    3. Lin YH, et al.
    Identification the cross-reactive or species-specific allergens of Tyrophagus putrescentiae and development molecular diagnostic kits for allergic diseases. Diagnostics 2020; 10: 665. doi:10.3390/diagnostics10090665
    OpenUrl
    1. Shen CY,
    2. Yen CY,
    3. Chien DK, et al.
    Influence of storage conditions on the infestation of Tyrophagus putrescentiae and prevalence of mite hypersensitivity in Taiwan. Exp Appl Acarol 2020; 80: 381–398. doi:10.1007/s10493-019-00453-6
    OpenUrl
  111. ↵
    1. Chevigne A,
    2. Jacquet A
    . Emerging roles of the protease allergen Der p 1 in house dust mite-induced airway inflammation. J Allergy Clin Immunol 2018; 142: 398–400. doi:10.1016/j.jaci.2018.05.027
    OpenUrl
  112. ↵
    1. Abu Khweek A,
    2. Kim E,
    3. Joldrichsen MR, et al.
    Insights into mucosal innate immune responses in house dust mite-mediated allergic asthma. Front Immunol 2020; 11: 534501. doi:10.3389/fimmu.2020.534501
    OpenUrl
  113. ↵
    1. Soh WT,
    2. Zhang J,
    3. Hollenberg MD, et al.
    Protease allergens as initiators-regulators of allergic inflammation. Allergy 2023; 78: 1148–1168. doi:10.1111/all.15678
    OpenUrl
  114. ↵
    1. Sudha VT,
    2. Arora N,
    3. Singh BP
    . Serine protease activity of Per a 10 augments allergen-induced airway inflammation in a mouse model. Eur J Clin Invest 2009; 39: 507–516. doi:10.1111/j.1365-2362.2009.02112.x
    OpenUrlCrossRefPubMed
  115. ↵
    1. Ring PC,
    2. Wan H,
    3. Schou C, et al
    . The 18-kDa form of cat allergen Felis domesticus 1 (Fel d 1) is associated with gelatin- and fibronectin-degrading activity. Clin Exp Allergy 2000; 30: 1085–1096. doi:10.1046/j.1365-2222.2000.00805.x.
    OpenUrlCrossRefPubMed
  116. ↵
    1. Hellings PW,
    2. Steelant B
    . Epithelial barriers in allergy and asthma. J Allergy Clin Immunol 2020; 145: 1499–1509. doi:10.1016/j.jaci.2020.04.010
    OpenUrl
  117. ↵
    1. Hewitt RJ,
    2. Lloyd CM
    . Regulation of immune responses by the airway epithelial cell landscape. Nat Rev Immunol 2021; 21: 347–362. doi:10.1038/s41577-020-00477-9
    OpenUrlCrossRefPubMed
  118. ↵
    1. Bustamante-Marin XM,
    2. Ostrowski LE
    . Cilia and mucociliary clearance. Cold Spring Harb Perspect Biol 2017; 9: a028241. doi:10.1101/cshperspect.a028241
    OpenUrlAbstract/FREE Full Text
  119. ↵
    1. Cho HJ,
    2. Choi JY,
    3. Yang YM, et al.
    House dust mite extract activates apical Cl- channels through protease-activated receptor 2 in human airway epithelia. J Cell Biochem 2010; 109: 1254–1263. doi:10.1002/jcb.22511
    OpenUrlCrossRefPubMed
  120. ↵
    1. McMahon DB,
    2. Workman AD,
    3. Kohanski MA, et al.
    Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating. FASEB J 2018; 32: 155–167. doi:10.1096/fj.201700114RRR
    OpenUrlCrossRefPubMed
  121. ↵
    1. Otani T,
    2. Furuse M
    . Tight junction structure and function revisited. Trends Cell Biol 2020; 30: 805–817. doi:10.1016/j.tcb.2020.08.004
    OpenUrlCrossRef
  122. ↵
    1. Nekrasova O,
    2. Green KJ
    . Desmosome assembly and dynamics. Trends Cell Biol 2013; 23: 537–546. doi:10.1016/j.tcb.2013.06.004
    OpenUrlCrossRefPubMed
  123. ↵
    1. Leino MS,
    2. Loxham M,
    3. Blume C, et al.
    Barrier disrupting effects of Alternaria alternata extract on bronchial epithelium from asthmatic donors. PloS One 2013; 8: e71278. doi:10.1371/journal.pone.0071278
    OpenUrlCrossRefPubMed
  124. ↵
    1. Tomee JF,
    2. Wierenga AT,
    3. Hiemstra PS, et al.
    Proteases from Aspergillus fumigatus induce release of proinflammatory cytokines and cell detachment in airway epithelial cell lines. J Infect Dis 1997; 176: 300–303. doi:10.1086/517272
    OpenUrlCrossRefPubMed
  125. ↵
    1. Tai HY,
    2. Tam MF,
    3. Chou H, et al.
    Pen ch 13 allergen induces secretion of mediators and degradation of occludin protein of human lung epithelial cells. Allergy 2006; 61: 382–388. doi:10.1111/j.1398-9995.2005.00958.x
    OpenUrlCrossRefPubMed
  126. ↵
    1. Chen JC,
    2. Chuang JG,
    3. Su YY, et al.
    The protease allergen Pen c 13 induces allergic airway inflammation and changes in epithelial barrier integrity and function in a murine model. J Biol Chem 2011; 286: 26667–26679. doi:10.1074/jbc.M110.193987
    OpenUrlAbstract/FREE Full Text
  127. ↵
    1. Wan H,
    2. Winton HL,
    3. Soeller C, et al.
    The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy 2001; 31: 279–294. doi:10.1046/j.1365-2222.2001.00970.x
    OpenUrlCrossRefPubMed
  128. ↵
    1. Karaguzel D,
    2. Sarac BE,
    3. Akel Bilgic H, et al.
    House dust mite-derived allergens effect on matrix metalloproteases in airway epithelial cells. Exp Lung Res 2021; 47: 436–450. doi:10.1080/01902148.2021.1998734
    OpenUrl
  129. ↵
    1. Kim YH,
    2. Kim T,
    3. Ji KY, et al.
    A time-dependently regulated gene network reveals that Aspergillus protease affects mitochondrial metabolism and airway epithelial cell barrier function via mitochondrial oxidants. Free Radic Biol Med 2022; 185: 76–89. doi:10.1016/j.freeradbiomed.2022.04.013
    OpenUrl
  130. ↵
    1. Drake LY,
    2. Kita H
    . IL-33: biological properties, functions, and roles in airway disease. Immunol Rev 2017; 278: 173–184. doi:10.1111/imr.12552
    OpenUrlCrossRef
  131. ↵
    1. Cayrol C,
    2. Girard JP
    . Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev 2018; 281: 154–168. doi:10.1111/imr.12619
    OpenUrlCrossRefPubMed
  132. ↵
    1. Gasiuniene E,
    2. Janulaityte I,
    3. Zemeckiene Z, et al.
    Elevated levels of interleukin-33 are associated with allergic and eosinophilic asthma. Scand J Immunol 2019; 89: e12724. doi:10.1111/sji.12724
    OpenUrl
  133. ↵
    1. Mitchell PD,
    2. Salter BM,
    3. Oliveria JP, et al.
    IL-33 and its receptor ST2 after inhaled allergen challenge in allergic asthmatics. Int Arch Allergy Immunol 2018; 176: 133–142. doi:10.1159/000488015
    OpenUrl
  134. ↵
    1. Snelgrove RJ,
    2. Gregory LG,
    3. Peiró T, et al.
    Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations. J Allergy Clin Immunol 2014; 134: 583–92.e6. doi:10.1016/j.jaci.2014.02.002
    OpenUrlCrossRefPubMed
  135. ↵
    1. Fujisawa T,
    2. Katsumata H,
    3. Kato Y
    . House dust mite extract induces interleukin-9 expression in human eosinophils. Allergol Int 2008; 57: 141–146. doi:10.2332/allergolint.O-07-498
    OpenUrlCrossRefPubMed
  136. ↵
    1. Yasuda Y,
    2. Nagano T,
    3. Kobayashi K, et al.
    Group 2 innate lymphoid cells and the house dust mite-induced asthma mouse model. Cells 2020; 9: 1178. doi:10.3390/cells9051178
    OpenUrl
  137. ↵
    1. Ouyang X,
    2. Reihill JA,
    3. Douglas LEJ, et al.
    House dust mite allergens induce Ca2+ signalling and alarmin responses in asthma airway epithelial cells. Biochim Biophys Acta Mol Basis Dis 2024; 1870: 167079. doi:10.1016/j.bbadis.2024.167079
    OpenUrl
  138. ↵
    1. Brusilovsky M,
    2. Rochman M,
    3. Rochman Y, et al.
    Environmental allergens trigger type 2 inflammation through ripoptosome activation. Nat Immunol 2021; 22: 1316–1326. doi:10.1038/s41590-021-01011-2
    OpenUrl
  139. ↵
    1. Li Z,
    2. Ji S,
    3. Jiang ML, et al.
    The regulation and modification of GSDMD signaling in diseases. Front Immunol 2022; 13: 893912. doi:10.3389/fimmu.2022.893912
    OpenUrl
  140. ↵
    1. Chen W,
    2. Chen S,
    3. Yan C, et al.
    Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion. Nat Immunol 2022; 23: 1021–1030. doi:10.1038/s41590-022-01255-6
    OpenUrlCrossRef
  141. ↵
    1. Cayrol C,
    2. Duval A,
    3. Schmitt P, et al.
    Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nat Immunol 2018; 19: 375–385. doi:10.1038/s41590-018-0067-5
    OpenUrlCrossRefPubMed
  142. ↵
    1. Lefrançais E,
    2. Roga S,
    3. Gautier V, et al.
    IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci USA 2012; 109: 1673–1678. doi:10.1073/pnas.1115884109
    OpenUrlAbstract/FREE Full Text
  143. ↵
    1. Ramu S,
    2. Menzel M,
    3. Bjermer L, et al.
    Allergens produce serine proteases-dependent distinct release of metabolite DAMPs in human bronchial epithelial cells. Clin Exp Allergy 2018; 48: 156–166. doi:10.1111/cea.13071
    OpenUrl
  144. ↵
    1. Srisomboon Y,
    2. Iijima K,
    3. Colwell M, et al.
    Allergen-induced DNA release by the airway epithelium amplifies type 2 immunity. J Allergy Clin Immunol 2023; 151: 494–508.e6. doi:10.1016/j.jaci.2022.09.034
    OpenUrl
  145. ↵
    1. Day SB,
    2. Ledford JR,
    3. Zhou P, et al.
    German cockroach proteases and protease-activated receptor-2 regulate chemokine production and dendritic cell recruitment. J Innate Immun 2012; 4: 100–110. doi:10.1159/000329132
    OpenUrlPubMed
  146. ↵
    1. King C,
    2. Brennan S,
    3. Thompson PJ, et al.
    Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 1998; 161: 3645–3651. doi:10.4049/jimmunol.161.7.3645
    OpenUrlAbstract/FREE Full Text
  147. ↵
    1. Nadeem A,
    2. Al-Harbi NO,
    3. Ahmad SF, et al.
    Protease activated receptor-2 mediated upregulation of IL-17 receptor signaling on airway epithelial cells is responsible for neutrophilic infiltration during acute exposure of house dust mite allergens in mice. Chem Biol Interact 2019; 304: 52–60. doi:10.1016/j.cbi.2019.03.001
    OpenUrl
  148. ↵
    1. Wiesner DL,
    2. Merkhofer RM,
    3. Ober C, et al.
    Club Cell TRPV4 serves as a damage sensor driving lung allergic inflammation. Cell Host Microbe 2020; 27: 614–28.e6. doi:10.1016/j.chom.2020.02.006
    OpenUrl
  149. ↵
    1. Lin YP,
    2. Scappini E,
    3. Landaverde C, et al.
    Nuanced interactions between AKAP79 and STIM1 with Orai1 Ca2+ channels at endoplasmic reticulum-plasma membrane junctions sustain NFAT activation. Mol Cell Biol 2022; 42: e0017522. doi:10.1128/mcb.00175-22
    OpenUrl
  150. ↵
    1. Lambrecht BN,
    2. Hammad H,
    3. Fahy JV
    . The cytokines of asthma. Immunity 2019; 50: 975–991. doi:10.1016/j.immuni.2019.03.018
    OpenUrlPubMed
  151. ↵
    1. Eguiluz-Gracia I,
    2. Layhadi JA,
    3. Rondon C, et al.
    Mucosal IgE immune responses in respiratory diseases. Curr Opin Pharmacol 2019; 46: 100–107. doi:10.1016/j.coph.2019.05.009
    OpenUrl
  152. ↵
    1. Boitano S,
    2. Flynn AN,
    3. Sherwood CL, et al.
    Alternaria alternata serine proteases induce lung inflammation and airway epithelial cell activation via PAR2. Am J Physiol Lung Cell Mol Physiol 2011; 300: L605–L614. doi:10.1152/ajplung.00359.2010
    OpenUrlCrossRefPubMed
  153. ↵
    1. Goel C,
    2. Govindaraj D,
    3. Singh BP, et al.
    Serine protease Per a 10 from Periplaneta americana bias dendritic cells towards type 2 by upregulating CD86 and low IL-12 secretions. Clin Exp Allergy 2012; 42: 412–422. doi:10.1111/j.1365-2222.2011.03937.x
    OpenUrlCrossRefPubMed
    1. Agrawal K,
    2. Kale SL,
    3. Arora N
    . Protease activity of Per a 10 potentiates Th2 polarization by increasing IL-23 and OX40L. Eur J Immunol 2015; 45: 3375–3385. doi:10.1002/eji.201545734
    OpenUrl
  155. ↵
    1. Agrawal K,
    2. Arora N
    . Serine protease allergen favours Th2 responses via PAR-2 and STAT3 activation in murine model. Allergy 2018; 73: 569–575. doi:10.1111/all.13315
    OpenUrl
  156. ↵
    1. Tripathi P,
    2. Kukreja N,
    3. Singh BP, et al.
    Serine protease activity of Cur l 1 from Curvularia lunata augments Th2 response in mice. J Clin Immunol 2009; 29: 292–302. doi:10.1007/s10875-008-9261-9
    OpenUrlCrossRefPubMed
  157. ↵
    1. Carey RM,
    2. Freund JR,
    3. Hariri BM, et al.
    Polarization of protease-activated receptor 2 (PAR-2) signaling is altered during airway epithelial remodeling and deciliation. J Biol Chem 2020; 295: 6721–6740. doi:10.1074/jbc.RA120.012710
    OpenUrlAbstract/FREE Full Text
  158. ↵
    1. Oguma T,
    2. Asano K,
    3. Tomomatsu K, et al.
    Induction of mucin and MUC5AC expression by the protease activity of Aspergillus fumigatus in airway epithelial cells. J Immunol 2011; 187: 999–1005. doi:10.4049/jimmunol.1002257
    OpenUrlAbstract/FREE Full Text
  159. ↵
    1. Harkness LM,
    2. Ashton AW,
    3. Burgess JK
    . Asthma is not only an airway disease, but also a vascular disease. Pharmacol Ther 2015; 148: 17–33. doi:10.1016/j.pharmthera.2014.11.010
    OpenUrlCrossRefPubMed
  160. ↵
    1. Samitas K,
    2. Carter A,
    3. Kariyawasam HH, et al.
    Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the one airway concept revisited. Allergy 2018; 73: 993–1002. doi:10.1111/all.13373
    OpenUrl
  161. ↵
    1. Burgstaller G,
    2. Oehrle B,
    3. Gerckens M, et al.
    The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease. Eur Respir J 2017; 50: 1601805. doi:10.1183/13993003.01805-2016
    OpenUrlAbstract/FREE Full Text
  162. ↵
    1. Ma HP,
    2. Li W,
    3. Liu XM
    . Matrix metalloproteinase 9 is involved in airway inflammation in cough variant asthma. Exp Ther Med 2014; 8: 1197–1200. doi:10.3892/etm.2014.1903
    OpenUrl
  163. ↵
    1. Øya E,
    2. Afanou AKJ,
    3. Malla N, et al.
    Characterization and pro-inflammatory responses of spore and hyphae samples from various mold species. Indoor Air 2018; 28: 28–39. doi:10.1111/ina.12426
    OpenUrl
  164. ↵
    1. Page K,
    2. Hughes VS,
    3. Bennett GW, et al.
    German cockroach proteases regulate matrix metalloproteinase-9 in human bronchial epithelial cells. Allergy 2006; 61: 988–995. doi:10.1111/j.1398-9995.2006.01103.x
    OpenUrlCrossRefPubMed
  165. ↵
    1. Barbaro MP,
    2. Spanevello A,
    3. Palladino GP, et al.
    Exhaled matrix metalloproteinase-9 (MMP-9) in different biological phenotypes of asthma. Eur J Intern Med 2014; 25: 92–96. doi:10.1016/j.ejim.2013.08.705
    OpenUrlCrossRefPubMed
  166. ↵
    1. Hughes VS,
    2. Page K
    . German cockroach frass proteases cleave pro-matrix metalloproteinase-9. Exp Lung Res 2007; 33: 135–150. doi:10.1080/01902140701356561
    OpenUrlCrossRefPubMed
  167. ↵
    1. Basu T,
    2. Seyedmousavi S,
    3. Sugui JA, et al.
    Aspergillus fumigatus alkaline protease 1 (Alp1/Asp f13) in the airways correlates with asthma severity. J Allergy Clin Immunol 2018; 141: 423–425.e7. doi:10.1016/j.jaci.2017.07.034
    OpenUrl
  168. ↵
    1. Balenga NA,
    2. Klichinsky M,
    3. Xie Z, et al.
    A fungal protease allergen provokes airway hyper-responsiveness in asthma. Nat Commun 2015; 6: 6763. doi:10.1038/ncomms7763
    OpenUrlCrossRefPubMed
  169. ↵
    1. Namvar S,
    2. Warn P,
    3. Farnell E, et al.
    Aspergillus fumigatus proteases, Asp f 5 and Asp f 13, are essential for airway inflammation and remodelling in a murine inhalation model. Clin Exp Allergy 2015; 45: 982–993. doi:10.1111/cea.12426
    OpenUrlCrossRefPubMed
  170. ↵
    1. Chandrabalan A,
    2. Ramachandran R
    . Molecular mechanisms regulating proteinase-activated receptors (PARs). FEBS J 2021; 288: 2697–2726. doi:10.1111/febs.15829
    OpenUrl
  171. ↵
    1. Zhang H,
    2. Zeng X,
    3. He S
    . Evaluation on potential contributions of protease activated receptors related mediators in allergic inflammation. Mediators Inflamm 2014; 2014: 829068. doi:10.1155/2014/829068
    OpenUrl
    1. Redes JL,
    2. Basu T,
    3. Ram-Mohan S, et al.
    Aspergillus fumigatus-secreted alkaline protease 1 mediates airways hyperresponsiveness in severe asthma. Immunohorizons 2019; 3: 368–377. doi:10.4049/immunohorizons.1900046
    OpenUrlAbstract/FREE Full Text
    1. Dietz CJ,
    2. Sun H,
    3. Yao WC, et al.
    Aspergillus fumigatus induction of IL-33 expression in chronic rhinosinusitis is PAR2-dependent. Laryngoscope 2019; 129: 2230–2235. doi:10.1002/lary.28000
    OpenUrl
    1. Rivas CM,
    2. Schiff HV,
    3. Moutal A, et al.
    Alternaria alternata-induced airway epithelial signaling and inflammatory responses via protease-activated receptor-2 expression. Biochem Biophys Res Commun 2022; 591: 13–19. doi:10.1016/j.bbrc.2021.12.090
    OpenUrl
    1. Yee MC,
    2. Nichols HL,
    3. Polley D, et al.
    Protease-activated receptor-2 signaling through β-arrestin-2 mediates Alternaria alkaline serine protease-induced airway inflammation. Am J Physiol Lung Cell Mol Physiol 2018; 315: L1042–L1l57. doi:10.1152/ajplung.00196.2018
    OpenUrl
    1. Kouzaki H,
    2. O'Grady SM,
    3. Lawrence CB, et al.
    Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2. J Immunol 2009; 183: 1427–1434. doi:10.4049/jimmunol.0900904
    OpenUrlAbstract/FREE Full Text
    1. Lee M-F,
    2. Wang NM,
    3. Liu S-W, et al.
    Induction of interleukin 8 by American cockroach allergens from human airway epithelial cells via extracellular signal regulatory kinase and jun N-terminal kinase but not p38 mitogen-activated protein kinase. Ann Allergy Asthma Immunol 2010; 105: 234–240. doi:10.1016/j.anai.2010.07.008
    OpenUrlPubMed
    1. Lutfi R,
    2. Lewkowich IP,
    3. Zhou P, et al.
    The role of protease-activated receptor-2 on pulmonary neutrophils in the innate immune response to cockroach allergen. J Inflamm 2012; 9: 32. doi:10.1186/1476-9255-9-32
    OpenUrl
    1. Page K,
    2. Strunk VS,
    3. Hershenson MB
    . Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)-2 and extracellular-signal-regulated kinase. J Allergy Clin Immunol 2003; 112: 1112–1118. doi:10.1016/j.jaci.2003.08.050
    OpenUrlCrossRefPubMed
    1. Day SB,
    2. Zhou P,
    3. Ledford JR, et al.
    German cockroach frass proteases modulate the innate immune response via activation of protease-activated receptor-2. J Innate Immun 2010; 2: 495–504. doi:10.1159/000317195
    OpenUrlCrossRefPubMed
    1. Kim JY,
    2. Sohn JH,
    3. Choi JM, et al.
    Alveolar macrophages play a key role in cockroach-induced allergic inflammation via TNF-α pathway. PloS One 2012; 7: e47971. doi:10.1371/journal.pone.0047971
    OpenUrlCrossRefPubMed
    1. Wang YJ,
    2. Yu SJ,
    3. Tsai JJ, et al.
    Antagonism of protease activated receptor-2 by GB88 reduces inflammation triggered by protease allergen Tyr-p3. Front Immunol 2021; 12: 557433. doi:10.3389/fimmu.2021.557433
    OpenUrlCrossRef
    1. Lin YP,
    2. Nelson C,
    3. Kramer H, et al.
    The allergen Der p3 from house dust mite stimulates store-operated Ca2+ channels and mast cell migration through PAR4 receptors. Mol Cell 2018; 70: 228–241.e5. doi:10.1016/j.molcel.2018.03.025
    OpenUrl
    1. Cho HJ,
    2. Lee HJ,
    3. Kim SC, et al.
    Protease-activated receptor 2-dependent fluid secretion from airway submucosal glands by house dust mite extract. J Allergy Clin Immunol 2012; 129: 529–535, 535.e1–5. doi:10.1016/j.jaci.2011.11.024
    OpenUrlCrossRefPubMed
    1. Post S,
    2. Heijink IH,
    3. Petersen AH, et al.
    Protease-activated receptor-2 activation contributes to house dust mite-induced IgE responses in mice. PloS One 2014; 9: e91206. doi:10.1371/journal.pone.0091206
    OpenUrlCrossRefPubMed
    1. Gu Q,
    2. Lee LY
    . House dust mite potentiates capsaicin-evoked Ca2+ transients in mouse pulmonary sensory neurons via activation of protease-activated receptor-2. Exp Physiol 2012; 97: 534–543. doi:10.1113/expphysiol.2011.060764
    OpenUrlCrossRefPubMed
    1. Gaspar R,
    2. de Matos MR,
    3. Cortes L, et al.
    Pollen proteases play multiple roles in allergic disorders. Int J Mol Sci 2020; 21: 3578. doi:10.3390/ijms21103578
    OpenUrl
  188. ↵
    1. Knight DA,
    2. Lim S,
    3. Scaffidi AK, et al.
    Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J Allergy Clin Immunol 2001; 108: 797–803. doi:10.1067/mai.2001.119025
    OpenUrlCrossRefPubMed
  189. ↵
    1. Lee-Rivera I,
    2. Lopez E,
    3. Lopez-Colome AM
    . Diversification of PAR signaling through receptor crosstalk. Cell Mol Biol Lett 2022; 27: 77. doi:10.1186/s11658-022-00382-0
    OpenUrl
  190. ↵
    1. Nadeem A,
    2. Alharbi NO,
    3. Vliagoftis H, et al.
    Proteinase activated receptor-2-mediated dual oxidase-2 up-regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma. Immunology 2015; 145: 391–403. doi:10.1111/imm.12453
    OpenUrlCrossRefPubMed
  191. ↵
    1. Jacquet A,
    2. Robinson C
    . Proteolytic, lipidergic and polysaccharide molecular recognition shape innate responses to house dust mite allergens. Allergy 2020; 75: 33–53. doi:10.1111/all.13940
    OpenUrl
  192. ↵
    1. Hadebe S,
    2. Brombacher F,
    3. Brown GD
    . C-type lectin receptors in asthma. Front Immunol 2018; 9: 733. doi:10.3389/fimmu.2018.00733
    OpenUrlCrossRefPubMed
  193. ↵
    1. Kim HJ,
    2. Kim H,
    3. Lee JH, et al.
    Toll-like receptor 4 (TLR4): new insight immune and aging. Immun Ageing 2023; 20: 67. doi:10.1186/s12979-023-00383-3
    OpenUrl
  194. ↵
    1. Millien VO,
    2. Lu W,
    3. Shaw J, et al.
    Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 2013; 341: 792–796. doi:10.1126/science.1240342
    OpenUrlAbstract/FREE Full Text
  195. ↵
    1. Landers CT,
    2. Tung HY,
    3. Knight JM, et al.
    Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b. J Biol Chem 2019; 294: 8834–8847. doi:10.1074/jbc.RA118.006724
    OpenUrlAbstract/FREE Full Text
  196. ↵
    1. Griffiths JS,
    2. Thompson A,
    3. Stott M, et al.
    Differential susceptibility of Dectin-1 isoforms to functional inactivation by neutrophil and fungal proteases. FASEB J 2018; 32: 3385–3397. doi:10.1096/fj.201701145R
    OpenUrl
  197. ↵
    1. Köhl J,
    2. Wills-Karp M
    . A dual role for complement in allergic asthma. Curr Opin Pharmacol 2007; 7: 283–289. doi:10.1016/j.coph.2007.01.005
    OpenUrlCrossRefPubMed
  198. ↵
    1. Drouin SM,
    2. Corry DB,
    3. Hollman TJ, et al.
    Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J Immunol 2002; 169: 5926–5933. doi:10.4049/jimmunol.169.10.5926
    OpenUrlAbstract/FREE Full Text
  199. ↵
    1. Gour N,
    2. Smole U,
    3. Yong HM, et al.
    C3a is required for ILC2 function in allergic airway inflammation. Mucosal Immunol 2018; 11: 1653–1662. doi:10.1038/s41385-018-0064-x
    OpenUrl
  200. ↵
    1. Aghapour M,
    2. Ubags ND,
    3. Bruder D, et al.
    Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD. Eur Respir Rev 2022; 31: 210112. doi:10.1183/16000617.0112-2021
    OpenUrlAbstract/FREE Full Text
  201. ↵
    1. Rusznak C,
    2. Sapsford RJ,
    3. Devalia JL, et al.
    Cigarette smoke potentiates house dust mite allergen-induced increase in the permeability of human bronchial epithelial cells in vitro. Am J Respir Cell Mol Biol 1999; 20: 1238–1250. doi:10.1165/ajrcmb.20.6.3226
    OpenUrlCrossRefPubMed
  202. ↵
    1. Loxham M,
    2. Smart DE,
    3. Bedke NJ, et al.
    Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of rhinovirus. Mucosal Immunol 2018; 11: 404–414. doi:10.1038/mi.2017.63
    OpenUrlCrossRef
  203. ↵
    1. Hoffmann M,
    2. Kleine-Weber H,
    3. Schroeder S, et al.
    SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271–80.e8. doi:10.1016/j.cell.2020.02.052
    OpenUrlCrossRefPubMed
  204. ↵
    1. Radzikowska U,
    2. Ding M,
    3. Tan G, et al.
    Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy 2020; 75: 2829–2845. doi:10.1111/all.14429
    OpenUrlPubMed
  205. ↵
    1. Kimura H,
    2. Francisco D,
    3. Conway M, et al.
    Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells. J Allergy Clin Immunol 2020; 146: 80–88.e8. doi:10.1016/j.jaci.2020.05.004
    OpenUrlCrossRefPubMed
  206. ↵
    1. Whetstone CE,
    2. Ranjbar M,
    3. Cusack RP, et al.
    Protein expression of SARS-CoV-2 receptors ACE2 and TMPRSS2 in allergic airways after allergen challenge. Allergy 2023; 78: 3010–3013. doi:10.1111/all.15793
    OpenUrl
  207. ↵
    1. Voynow JA,
    2. Shinbashi M
    . Neutrophil elastase and chronic lung disease. Biomolecules 2021; 11: 1065. doi:10.3390/biom11081065
    OpenUrlCrossRef
  208. ↵
    1. Chalmers JD,
    2. Haworth CS,
    3. Metersky ML, et al.
    Phase 2 Trial of the DPP-1 inhibitor brensocatib in bronchiectasis. N Engl J Med 2020; 383: 2127–2137. doi:10.1056/NEJMoa2021713
    OpenUrlPubMed
  209. ↵
    1. Chakraborti S,
    2. Chakraborti T,
    3. Dhalla NS
    1. Chakraborti S,
    2. Sarkar J,
    3. Pramanik PK, et al.
    Role of proteases in lung disease: a brief overview. In: Chakraborti S, Chakraborti T, Dhalla NS, eds. Proteases in Human Diseases. Singapore, Springer Singapore, 2017; pp. 333–374.
  210. ↵
    1. Pejler G
    . The emerging role of mast cell proteases in asthma. Eur Respir J 2019; 54: 1900685. doi:10.1183/13993003.00685-2019
    OpenUrlAbstract/FREE Full Text
  211. ↵
    1. Koga H,
    2. Miyahara N,
    3. Fuchimoto Y, et al.
    Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses. Respir Res 2013; 14: 8. doi:10.1186/1465-9921-14-8
    OpenUrlCrossRefPubMed
  212. ↵
    1. Kouzaki H,
    2. Matsumoto K,
    3. Kikuoka H, et al.
    Endogenous protease inhibitors in airway epithelial cells contribute to eosinophilic chronic rhinosinusitis. Am J Respir Crit Care Med 2017; 195: 737–747. doi:10.1164/rccm.201603-0529OC
    OpenUrl
  213. ↵
    1. Cazzola M,
    2. Stolz D,
    3. Rogliani P, et al.
    α1-Antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev 2020; 29: 190073. doi:10.1183/16000617.0073-2019
    OpenUrlAbstract/FREE Full Text
  214. ↵
    1. Raby KL,
    2. Michaeloudes C,
    3. Tonkin J, et al.
    Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD. Front Immunol 2023; 14: 1201658. doi:10.3389/fimmu.2023.1201658
    OpenUrl
  215. ↵
    1. Strnad P,
    2. McElvaney NG,
    3. Lomas DA
    . α1-Antitrypsin deficiency. N Engl J Med 2020; 382: 1443–1455. doi:10.1056/NEJMra1910234
    OpenUrlCrossRef
  216. ↵
    1. Miravitlles M,
    2. Anzueto A,
    3. Barrecheguren M
    . Nine controversial questions about augmentation therapy for alpha-1 antitrypsin deficiency: a viewpoint. Eur Respir Rev 2023; 32: 230170. doi:10.1183/16000617.0170-2023
    OpenUrlAbstract/FREE Full Text
  217. ↵
    1. Kelly-Robinson GA,
    2. Reihill JA,
    3. Lundy FT, et al.
    The serpin superfamily and their role in the regulation and dysfunction of serine protease activity in COPD and other chronic lung diseases. Int J Mol Sci 2021; 22: 6351. doi:10.3390/ijms22126351
    OpenUrl
  218. ↵
    1. Shamji MH,
    2. Temblay JN,
    3. Cheng W, et al.
    Antiapoptotic serine protease inhibitors contribute to survival of allergenic TH2 cells. J Allergy Clin Immunol 2018; 142: 569–581.e5. doi:10.1016/j.jaci.2017.07.055
    OpenUrl
  219. ↵
    1. Mo Y,
    2. Ye L,
    3. Cai H, et al.
    SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells. Respir Res 2021; 22: 178. doi:10.1186/s12931-021-01757-1
    OpenUrl
  220. ↵
    1. Chen TY,
    2. Zhou M,
    3. Lin MQ, et al.
    Research progress on the SERPINE1 protein and chronic inflammatory diseases of the upper respiratory tract: a literature review. Int Arch Allergy Immunol 2021; 182: 1097–1102. doi:10.1159/000516195
    OpenUrl
  221. ↵
    1. Hu C,
    2. Jiang J,
    3. Xun Q, et al.
    Inhibition of SERPINE2/protease nexin-1 by a monoclonal antibody attenuates airway remodeling in a murine model of asthma. Int J Clin Exp Pathol 2017; 10: 11838–11848.
    OpenUrl
  222. ↵
    1. Scuri M,
    2. Botvinnikova Y,
    3. Lauredo IT, et al.
    Recombinant α1-proteinase inhibitor blocks antigen- and mediator-induced airway responses in sheep. J Appl Physiol 2002; 93: 1900–1906. doi:10.1152/japplphysiol.00400.2002
    OpenUrlCrossRefPubMed
    1. Fujimoto K,
    2. Kubo K,
    3. Shinozaki S, et al.
    Neutrophil elastase inhibitor reduces asthmatic responses in allergic sheep. Respir Physiol 1995; 100: 91–100. doi:10.1016/0034-5687(94)00123-H
    OpenUrlCrossRefPubMed
    1. Song D,
    2. Song G,
    3. Niu Y, et al.
    Ulinastatin activates haem oxygenase 1 antioxidant pathway and attenuates allergic inflammation. Br J Pharmacol 2014; 171: 4399–4412. doi:10.1111/bph.12780
    OpenUrlCrossRefPubMed
  225. ↵
    1. Reihill JA,
    2. Ouyang X,
    3. Yang Z, et al.
    A novel serine protease inhibitor PE-BBI ameliorates cockroach extract-mediated airway epithelial barrier dysfunction. Biomolecules 2020; 10: 515. doi:10.3390/biom10040515
    OpenUrl
    1. Soto AS,
    2. Fenoy IM,
    3. Sanchez VR, et al.
    Toxoplasma gondii serine-protease inhibitor-1: a new adjuvant candidate for asthma therapy. PloS One 2017; 12: e0187002. doi:10.1371/journal.pone.0187002
    OpenUrl
    1. Saw S,
    2. Arora N
    . Protease inhibitor reduces airway response and underlying inflammation in cockroach allergen-induced murine model. Inflammation 2015; 38: 672–682. doi:10.1007/s10753-014-9976-0
    OpenUrl
    1. Lee MF,
    2. Chang CW,
    3. Wang NM, et al.
    Serine protease inhibitor gabexate mesilate attenuates American cockroach-induced bronchial damage and inflammatory cytokine release. J Investig Allergol Clin Immunol 2014; 24: 338–345.
    OpenUrl
  229. ↵
    1. Ishizaki M,
    2. Tanaka H,
    3. Kajiwara D, et al.
    Nafamostat mesilate, a potent serine protease inhibitor, inhibits airway eosinophilic inflammation and airway epithelial remodeling in a murine model of allergic asthma. J Pharmacol Sci 2008; 108: 355–363. doi:10.1254/jphs.08162FP
    OpenUrl
    1. Chen CL,
    2. Wang SD,
    3. Zeng ZY, et al.
    Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma. J Allergy Clin Immunol 2006; 118: 105–112. doi:10.1016/j.jaci.2006.02.047
    OpenUrlCrossRefPubMed
  231. ↵
    1. Nakayama F
    . Panniculitis with eosinophilic infiltration due to gabexate mesilate (FOY): possibility of allergic reaction. J Dermatol 1997; 24: 235–242. doi:10.1111/j.1346-8138.1997.tb02780.x
    OpenUrlPubMed
  232. ↵
    1. Lyu P,
    2. Ge L,
    3. Ma R, et al.
    Identification and pharmaceutical evaluation of novel frog skin-derived serine proteinase inhibitor peptide-PE-BBI (Pelophylax esculentus Bowman–Birk inhibitor) for the potential treatment of cancer. Sci Rep 2018; 8: 14502. doi:10.1038/s41598-018-32947-5
    OpenUrl
  233. ↵
    1. Ferguson TEG,
    2. Reihill JA,
    3. Martin SL, et al.
    Novel inhibitors and activity-based probes targeting trypsin-like serine proteases. Front Chem 2022; 10: 782608. doi:10.3389/fchem.2022.782608
    OpenUrl
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Airborne indoor allergen serine proteases and their contribution to sensitisation and activation of innate immunity in allergic airway disease
Xuan Ouyang, James A. Reihill, Lisa E.J. Douglas, S. Lorraine Martin
European Respiratory Review Apr 2024, 33 (172) 230126; DOI: 10.1183/16000617.0126-2023
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