Trends in Immunology
ReviewInnate immune cells in asthma
Introduction
Asthma is a disease from the conducting airways leading to various degrees of airflow obstruction and to airway hyper-responsiveness (AHR) [1]. The inflammation developed in asthmatic lungs contributes to the pathophysiology of the disease. This occurs mostly through the release of inflammatory mediators and the remodeling of the airways. Most of the asthma features are due to an aberrant expansion of Th2 lymphocytes that secrete type-2 cytokines such as interleukin (IL)-4, IL-5, IL-9, and IL-13 [2]. Attempts have been made to block selectively cytokines, chemokines, and pathways associated with the adaptive immune part of the disease. However, this type of approach has allowed in some cases to help only some subsets of asthmatic patients [3]. Recent discoveries in the field increasingly show that the innate cells control crucial aspects of the disease. A newly identified innate cell population, called ILC2, was found to be phenotypically and functionally very close to Th2 cells 4, 5. The function of innate cells [mast cells (MCs), basophils, eosinophils, and DCs] in asthma has been extensively studied using genetic or antibody-based depletion strategies. However, in most cases, these studies have brought controversies or confusion in the field because of bystander effects induced by the different depleting strategies. The role of ILC2s is equally controversial because they cannot be specifically depleted, and most of the work done to address their functions has been done in immunodeficient mice, rendering the results difficult to interpret. Also, during inflammatory processes, innate cells are involved in complex multidirectional interactions, sometimes show overlapping functions, and can easily compensate for each other. Here, we discuss the individual role of different innate cells involved in the pathogenesis of allergic asthma, and how they need to interact to orchestrate Th2 immunity.
Section snippets
MCs contribute to allergic asthma through IgE-dependent and -independent mechanisms
MCs arise in the bone marrow but classically reside in tissues, where they can survive for months or even years. In an allergic individual, whose tissue MCs already have antigen-specific IgE bound to FcɛRI (the high affinity IgE receptor), re-exposure to the allergens results in the crosslinking of neighboring FcɛRI-bound IgE and in the aggregation of surface FcɛRI. If such aggregation is long enough, it will trigger MCs to release diverse mediators that play an important role in the immediate
Basophils are accessory cells providing Th2 cytokines in asthma
Basophils are phenotypically and functionally related to MCs. Just like MCs, basophils express the high affinity receptor FcɛRI and produce similar sets of mediators, including histamine, Th2-associated cytokines, and lipid mediators. Mature basophils have a short life span (∼60 h) under steady-state conditions [27] but this can increase during inflammation. The main cytokine driving basophil development is IL-3, which is produced by T cells and drives basophil recruitment to LNs 28, 29. More
Eosinophils: an early source of Th2 cytokines in asthma
Eosinophils are associated with the pathogenesis of asthma, and their accumulation in the lungs is often regarded as a defining feature of allergic asthma in humans and animal models. The exact role of these cells in asthma has remained enigmatic for several decades. It was assumed that eosinophils were recruited to the lungs by Th2 cells as end-stage effector cells. As such, patients with allergic asthma have increased amounts of IL-5 in the bronchoalveolar lavage (BAL) fluids [46]. In
Neutrophils are recruited to the lungs of patients with severe asthma
Although asthma has been associated with the presence of eosinophils for a long time, it has become increasingly evident in recent years that some asthmatics have prominent neutrophilic inflammation. The precise role of neutrophils in the pathogenesis of asthma is difficult to understand, especially since the classical treatment with glucocorticoids can prolong neutrophil survival [70]. In addition, the exposure to smoking may also increase neutrophilic inflammation [71]. Until now, it is
DC and epithelial cell crosstalk is crucial in Th2 immunity to inhaled allergens
Th2 responses in asthma require antigen presentation by DCs 31, 34, 38. Lung DCs are made of different subsets. In the absence of inflammation, lung conventional DCs (cDCs) can be subdivided into three distinct subsets based on the expression of a combination of specific cell surface markers and on their distinct ontogeny: CD103+ cDCs that belong to the CD8α-type; CD11b+ cDCs that belong to the CD11b-type; and plasmacytoid (p)DCs [74]. In addition, monocyte-derived DCs (moDCs) have been
ILC2s: new players in Th2 immunity
The mechanisms controlling the activation of innate immune cells in response to viral or bacterial infections have been well characterized. However, the contribution of ILCs to activation of Th2 responses has only recently become apparent.
These ILCs can serve as important sources of Th1, Th2, or Th17 cytokines and have been named ILC1, ILC2, and ILC3, respectively [94]. ILCs have similar morphologies to T cells but do not express T or B cell antigen receptors or markers of other lineages.
Interaction between innate cells and structural cells orchestrate Th2 responses
During sensitization to inhaled allergens, DCs play a pivotal role in driving Th2 responses in the lungs. However, these DC-driven responses are found to be heavily influenced by epithelium-derived cytokines (IL-33, IL-25, IL-1, and GM-CSF) 11, 12. After migrating to the draining LNs, lung-derived DCs activate naïve T cells to become effector Th2 cells. It is possible that, at this stage of the immune response to allergens, other innate cells such as basophils or eosinophils, recruited to the
Concluding remarks
It is increasingly clear that innate immune cells play a critical role in the pathophysiology of asthma. However, it is still unclear from most studies during which phase of the response innate cells are important. This has been particularly difficult mostly because models allowing the specific depletion of these populations at specific time points are lacking. So far, only the blockade of individual innate cytokines has emphasized a role for the lung epithelial cells in Th2 sensitization.
References (116)
Cytokine targets in airway inflammation
Curr. Opin. Pharmacol.
(2013)The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells
Immunity
(2012)Advances in mast cell biology: new understanding of heterogeneity and function
Mucosal Immunol.
(2010)- et al.
Basophil effector function and homeostasis during helminth infection
Blood
(2009) Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen
Immunity
(2013)Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths
Immunity
(2010)Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin
J. Allergy Clin. Immunol.
(2000)Migration and accumulation of eosinophils toward regional lymph nodes after airway allergen challenge
J. Allergy Clin. Immunol.
(2004)Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections
Mucosal Immunol.
(2013)An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma
Immunity
(2011)