Chest
Volume 145, Issue 5, May 2014, Pages 1121-1133
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Translating Basic Research into Clinical Practice
Inflammasomes in Respiratory Disease: From Bench to Bedside

https://doi.org/10.1378/chest.13-1885Get rights and content

The respiratory tract of human subjects is constantly exposed to harmful microbes and air pollutants. The immune system responds to these offenders to protect the host, but an unbalanced inflammatory response itself may promote tissue damage and ultimately lead to acute and chronic respiratory diseases. Deregulated inflammasome activation is emerging as a key modulator of respiratory infections and pathologic airway inflammation in patients with asthma, COPD, and pulmonary fibrosis. Assembly of these intracellular danger sensors in cells of the respiratory mucosa and alveolar compartment triggers a proinflammatory cell death mode termed pyroptosis and leads to secretion of bioactive IL-1β and IL-18. Here, we summarize and review the inflammasome and its downstream effectors as therapeutic targets for the treatment of respiratory diseases.

Section snippets

Inflammasomes: Platforms for Caspase-1 Activation

Inflammasomes are defined as intracellular multiprotein complexes that facilitate the proximity-induced autoactivation of the proinflammatory cysteine protease caspase-1. Similar to apical caspases activating the death receptor-mediated and the mitochondria-dependent apoptotic cell death pathways, caspase-1 is produced as an inactive protease zymogen that resides in the cytosol of myeloid and epithelial cells. Upon detection of endogenous or exogenous signals indicating imminent danger, sensor

Flu (Influenza A Virus)

Influenza A virus, a negative-stranded RNA virus, is a major cause of human respiratory infections and a frequent trigger of exacerbations in patients with asthma or COPD. Influenza A viruses are sensed by three different PRRs, namely the endosomal TLR7 that recognizes viral single-stranded RNA (ssRNA), the cytosolic retinoic acid-inducible gene-I receptor that senses viral ssRNA bearing 5′-triphosphates, and the NLRP3 inflammasome that activates caspase-1 in macrophages and dendritic cells.45

Asthma

A common denominator of chronic inflammatory lung diseases, such as asthma, COPD, and pulmonary fibrosis, is that they represent complex diseases that result from the interaction between genetic susceptibility and environmental exposures. Indeed, several findings suggest that the inflammasome pathway might be involved in the pathogenesis of asthma. First, genomewide association studies of asthma have shown a significant association with single-nucleotide polymorphisms within the IL18R1 gene on

Pharmacologic Targeting of Inflammasome Signaling

The inflammasome provides several promising targets for pharmacological intervention in respiratory infection and chronic lung inflammation. Modulation of inflammasome-dependent biologic outcomes may be accomplished at several levels, for instance by preventing the nuclear factor-κB-dependent upregulation of NLRP3 and the inflammasome substrates proIL-1β and proIL-18 (eg, BAY 11-7082); by inhibiting inflammasome assembly and activation by means of P2X7 antagonists, glyburide, or cytokine

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: There was no role for the funding bodies in writing and editing of the manuscript.

References (94)

  • IK Pang et al.

    Inflammasomes as mediators of immunity against influenza virus

    Trends Immunol

    (2011)
  • K Walter et al.

    NALP3 is not necessary for early protection against experimental tuberculosis

    Immunobiology

    (2010)
  • Y Hitomi et al.

    Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma

    J Allergy Clin Immunol

    (2009)
  • GG Brusselle et al.

    New insights into the immunology of chronic obstructive pulmonary disease

    Lancet

    (2011)
  • C Schorn et al.

    Sodium overload and water influx activate the NALP3 inflammasome

    J Biol Chem

    (2011)
  • T Li et al.

    Pharmacokinetics and anti-asthmatic potential of non-parenterally administered recombinant human interleukin-1 receptor antagonist in animal models

    J Pharmacol Sci

    (2006)
  • K Newton et al.

    Signaling in innate immunity and inflammation

    Cold Spring Harb Perspect Biol

    (2012)
  • M Lamkanfi et al.

    Inflammasomes and their roles in health and disease

    Annu Rev Cell Dev Biol

    (2012)
  • JE Sims et al.

    The IL-1 family: regulators of immunity

    Nat Rev Immunol

    (2010)
  • AA Wanderer

    Interleukin-1beta targeted therapy in severe persistent asthma (SPA) and chronic obstructive pulmonary disease (COPD): proposed similarities between biphasic pathobiology of SPA/COPD and ischemia-reperfusion injury

    Isr Med Assoc J

    (2008)
  • CM Artlett

    The role of the NLRP3 inflammasome in fibrosis

    Open Rheumatol J

    (2012)
  • CA Dinarello

    Immunological and inflammatory functions of the interleukin-1 family

    Annu Rev Immunol

    (2009)
  • M Lamkanfi

    Emerging inflammasome effector mechanisms

    Nat Rev Immunol

    (2011)
  • N Kayagaki et al.

    Non-canonical inflammasome activation targets caspase-11

    Nature

    (2011)
  • M Kovarova et al.

    NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice

    J Immunol

    (2012)
  • A Dunne et al.

    Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis

    J Immunol

    (2010)
  • XB He et al.

    Inflammation and fibrosis during Chlamydia pneumoniae infection is regulated by IL-1 and the NLRP3/ASC inflammasome

    J Immunol

    (2010)
  • K Shimada et al.

    Caspase-1 dependent IL-1β secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection

    PLoS ONE

    (2011)
  • T Fernandes-Alnemri et al.

    The AIM2 inflammasome is critical for innate immunity to Francisella tularensis

    Nat Immunol

    (2010)
  • J Rotta Detto Loria et al.

    Nontypeable Haemophilus influenzae infection upregulates the NLRP3 inflammasome and leads to caspase-1-dependent secretion of interleukin-1b—a possible pathway of exacerbations in COPD

    PLoS One

    (2013)
  • SB Willingham et al.

    NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways

    J Immunol

    (2009)
  • S Cai et al.

    NLRC4 inflammasome-mediated production of IL-1β modulates mucosal immunity in the lung against gram-negative bacterial infection

    J Immunol

    (2012)
  • KL Lightfield et al.

    Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin

    Nat Immunol

    (2008)
  • S Mariathasan et al.

    Cryopyrin activates the inflammasome in response to toxins and ATP

    Nature

    (2006)
  • RR Craven et al.

    Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells

    PLoS ONE

    (2009)
  • R Fang et al.

    Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection

    J Immunol

    (2011)
  • M Witzenrath et al.

    The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia

    J Immunol

    (2011)
  • N Saïd-Sadier et al.

    Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase

    PLoS ONE

    (2010)
  • O Gross et al.

    Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence

    Nature

    (2009)
  • S Joly et al.

    Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome

    J Immunol

    (2009)
  • BB Mishra et al.

    Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome

    Cell Microbiol

    (2010)
  • H Saiga et al.

    Critical role of AIM2 in Mycobacterium tuberculosis infection

    Int Immunol

    (2012)
  • KW Wong et al.

    Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis

    Cell Microbiol

    (2011)
  • NP Juffermans et al.

    Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis

    J Infect Dis

    (2000)
  • VAK Rathinam et al.

    The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses

    Nat Immunol

    (2010)
  • T Ichinohe et al.

    Influenza virus activates inflammasomes via its intracellular M2 ion channel

    Nat Immunol

    (2010)
  • T Ichinohe et al.

    Inflammasome recognition of influenza virus is essential for adaptive immune responses

    J Exp Med

    (2009)
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    Funding/Support: Work in Dr Lamkanfi's laboratory is supported in part by the European Union [Marie-Curie Grant 256432], European Research Council [Grant 281600], and the Fund for Scientific Research Flanders (FWO) [Grants G030212N, 1.2.201.10.N.00, and 1.5.122.11.N.00]. Drs Provoost and Bracke are postdoctoral researchers of FWO. Presented work within the Department of Respiratory Medicine of Ghent University is funded by grants from the FWO, the Concerted Action of Ghent University, and the Interuniversity Attraction Poles Program.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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