Abstract Asthma is a chronic inflammatory disease of the airways that is characterized by eosinophilic inflammation, mucus hypersecretion and airway remodeling that leads to airway obstruction. Although these pathognomonic features of asthma are primarily mediated by allergen-specific T helper type 2 cells (Th2 cells) and their cytokines, recent studies have revealed critical roles of lung epithelial cells in the pathogenesis of asthma. Lung epithelial cells not only form physical barriers by covering the surfaces of the airways but also sense inhaled allergens and initiate communication between the environment and the immune system. The causative involvement of lung epithelium in the pathogenesis of asthma suggests that some molecules that modulate epithelial function have a regulatory role in asthma. IL-22, an IL-10-family cytokine produced by IL-17A-producing T helper cells (Th17 cells), γδ T cells and group 3 innate lymphoid cells (ILC3s), primarily targets epithelial cells and promotes their proliferation. In addition, IL-22 has been shown to induce epithelial production of various molecules that regulate local immune responses. These findings indicate that IL-22 plays crucial roles in the pathogenesis of asthma by regulating epithelial function. Here, we review the current understanding of the molecular and cellular mechanisms underlying IL-22-mediated regulation of airway inflammation in asthma. epithelial cells, ILC3, Th17 cells Introduction Asthma is the most prevalent chronic respiratory disease and is characterized by repeated breathlessness, airway hyperresponsiveness and mucus hypersecretion (1, 2). These pathognomonic features are mainly mediated by allergen-specific T helper type 2 cells (Th2 cells) and their cytokines. Histopathologically, asthma is characterized by intense infiltration of eosinophils, mast cells and CD4+ T cells producing IL-4, IL-5 and IL-13, even in patients with non-atopic asthma (3, 4). Analyses of mice lacking each Th2 cytokine have provided strong evidence that Th2 cells and their cytokines can drive a series of pathognomonic features of asthma, including eosinophilic inflammation and airway hyperresponsiveness (5–7). In addition to murine studies, clinical trials showing that monoclonal antibodies against Th2 cytokines are effective for a considerable proportion of patients with asthma (8) have proven the importance of Th2-biased immune responses in human asthmatics. Regarding the mechanisms underlying the induction of Th2 cells in asthma, several studies have revealed that Th2 cell induction from naive T cells (Tn cells) in the lung is driven by dendritic cells (DCs) (9, 10). Furthermore, over the past several years, it has become clear that the barrier function of epithelium as well as epithelial cell-derived factors are profoundly involved in the induction of Th2-biased immune responses (11). Moreover, it has been suggested that intimate cross-talk between DCs and epithelial cells is crucial for the development of asthma (11). However, the precise mechanisms by which DCs and epithelial cells coordinately promote Th2 cell differentiation in asthma remain obscure. Because lung epithelial cells are constantly exposed to the outside world, it is crucial that airway epithelium functions as a first-line sentinel to inhaled environmental matter by expressing a series of innate pattern-recognition receptors, including Toll-like receptors, C-type lectin receptors and NOD-like receptors (11, 12). By sensing inhaled matter via these innate receptors, the airway epithelium produces a variety of cytokines and chemokines that activate and recruit inflammatory cells (11, 12). Importantly, it has recently been shown that some of the epithelial cytokines, such as IL-25, IL-33 and TSLP, have non-redundant roles in the initiation and maintenance of Th2-biased immune responses in the lung (11) (Fig. 1). Moreover, upon allergen exposure, lung epithelial cells release a series of endogenous danger signals, such as ATP, uric acids and DNA, which also function as initiators of Th2-biased immune responses (13). These findings suggest that the development of Th2-biased immune responses in the airways is largely dependent on the airway epithelium. Fig. 1. View largeDownload slide Schematic representation of the protective roles of IL-22 in allergic airway inflammation. Upon allergen inhalation, CD4+ T cells and ILC3s in the lung produce IL-22. (A) IL-22 inhibits the expression of lung epithelial cell-derived cytokines and attenuates the development of allergic airway inflammation. (B) IL-22 enhances the barrier function of airway epithelium, possibly through the regulation of epithelial stem cell proliferation. (C) IL-22 may regulate the development of allergic airway inflammation by altering the microbiome and/or metabolism. Fig. 1. View largeDownload slide Schematic representation of the protective roles of IL-22 in allergic airway inflammation. Upon allergen inhalation, CD4+ T cells and ILC3s in the lung produce IL-22. (A) IL-22 inhibits the expression of lung epithelial cell-derived cytokines and attenuates the development of allergic airway inflammation. (B) IL-22 enhances the barrier function of airway epithelium, possibly through the regulation of epithelial stem cell proliferation. (C) IL-22 may regulate the development of allergic airway inflammation by altering the microbiome and/or metabolism. Although accumulating evidence suggests the importance of airway epithelium in the immune responses in the lung, little is known about the regulatory mechanism of epithelial function during allergic airway inflammation. The mechanisms underlying the restoration of epithelial function after injury are also largely unknown. One candidate molecule that may regulate these processes is IL-22, a cytokine belonging to the IL-10 family (14). Unlike IL-10, which mainly functions on hematopoietic cells, IL-22 preferentially functions on non-hematopoietic cells including epithelial cells and stromal cells in mucosal tissues (14). IL-22 has also been shown to exhibit a profound effect on the regeneration of epithelial tissues following injury and to play crucial roles in host defense in barrier tissues, including gut, skin and lung (14). In accordance with the widespread function of IL-22 in regeneration and host defense in epithelial tissues, several studies including ours have revealed critical roles of IL-22 in allergic airway inflammation (15–21). In this review, we discuss recent advances in cellular sources and targets of IL-22, and its roles in the pathogenesis of asthma. IL-22 and its receptor IL-22—originally named IL-10-related T-cell-derived inducible factor (IL-TIF) (22)—is a member of the IL-10 family of cytokines, along with IL-10, IL-19, IL-20, IL-24, IL-26, IL-28 (α and β) and IL-29 (14). The human IL22 gene is located at chromosome 12p15 near the genes encoding IFN-γ and IL-26 (23). Although early studies found constitutive expression of IL-22 in the thymus and brain (22), subsequent studies have shown its inducible expression in the gut, skin, pancreas, spleen and lung (24). The functional IL-22 receptor (IL-22R) is composed of two heterodimeric subunits IL-22R1 and IL-10R2 (25–27). Binding of IL-22 to the IL-22R results in the activation of two receptor-associated Janus kinases—Jak1 and Tyk2—leading to phosphorylation of STAT proteins (28). Although IL-22R activation induces the phosphorylation of STAT1, STAT3 and STAT5, it became clear that STAT3 is a primary mediator of IL-22 signaling (28). In addition to STAT proteins, IL-22 also activates MAP kinase and p38 pathways; however, the precise roles of these pathways in IL-22 signaling remain unclear (28). Importantly, whereas IL-10R2 is ubiquitously expressed in many cell types, IL-22R1 expression is restricted to cells within epithelial origin, such as epithelial cells in various tissues, hepatocytes and acinar cells, defining IL-22-target tissues as skin, intestine, liver, pancreas and lung (29). It is generally believed that IL-22 is vital to sustain the integrity and barrier function of these tissues and to prevent further damage by promoting cell survival and proliferation or by inducing inflammatory responses. Cellular sources of IL-22 IL-22 was originally identified in conventional T cells activated by IL-9 (22). Thereafter, cells in both innate and adaptive immune systems, including αβ T cells, γδ T cells, natural killer T cells (NKT cells) and innate lymphoid cells (ILCs) have been shown to produce IL-22 (14). In mice, IL-22 production by αβ T cells is largely attributed to IL-17A-producing Th cells (Th17 cells) (30, 31). In contrast, IL-22 production by human peripheral blood CD4+ T cells has been identified in Th1 cells, Th17 cells and Th22 cells (32). Besides CD4+ T cells, a subset of murine CD8+ T cells has been shown as a source of IL-22, especially in inflammatory conditions (33); however, the importance of IL-22 production by CD8+ T cells remains to be determined. In addition to the conventional αβ T cells, γδ T cells and NKT cells have been shown to produce IL-22 in mice (34–36). Like IL-22-producing CD4+ T cells, murine γδ T cells and NKT cells that express RORγt together with IL-23 receptor (IL-23R) produce IL-22 in response to IL-23 (34, 35). ILCs, a recently identified heterogeneous lymphoid cell subset that lacks the expression of rearranged T-cell and B-cell antigen receptors, have also been shown to produce IL-22 (37). To date, three different groups of ILCs that mirror the subsets of CD4+ T cells in terms of cytokine profiles and the expression of key transcription factors have been identified: namely, ILC1s, ILC2s and ILC3s. Among them, ILC3s are potent IL-22 producers (37). Another cellular source of IL-22 was reported to be a subset of NK cells that was designated as NK22 cells in humans (38–40). However, subsequent analyses using fate-mapping revealed that these cells seem to be distinct from NK cells (41) and thus reclassified as a subset of ILC3s (37). IL-22-producing populations in murine asthma models remain controversial. Some studies including ours have shown that CD4+ T cells are the main IL-22 producers (15, 16), whereas another study has reported ILCs as the main producers (18). However, we consider that these reports are not mutually exclusive, since it has been reported that, in murine intestine, IL-22 production from ILCs is essential for early defense against infection, whereas IL-22 production from CD4+ T cells contributes to the development of late-phase responses (42). Therefore, it is possible that CD4+ T cells and ILC3s produce IL-22 with different kinetics in asthma, and IL-22 produced by CD4+ T cells and ILC3s plays a distinct role in different phases in the pathogenesis of asthma. Regarding other potentially IL-22-producing cells, although it has been demonstrated that murine NKT cells produce IL-22 in the lung upon virus infection (43), there is no report about IL-22 production by NKT cells in murine asthma models. Protective roles of IL-22 in allergic airway inflammation in mice IL-22 is produced at the site of inflammation and its receptor is expressed on epithelial cells (14). In addition, previous studies have indicated that IL-22 is involved in physiological repair processes and protection against local damage (14). On the other hand, IL-22 has been shown to induce the expression of pro-inflammatory molecules (14). These findings lead to conflicting predictions as to whether IL-22 is a protective or a pro-inflammatory cytokine in asthma. Consistent with the conflict, studies investigating the role of IL-22 in murine asthma models came to different conclusions. Several murine studies including ours have shown that IL-22 has a protective role in the development of allergic airway inflammation (15–19). We and another group demonstrated that antibody-mediated neutralization of IL-22 during the allergen challenge phase significantly enhances inflammatory cell infiltration and Th2 cytokine production in bronchoalveolar lavage fluid in sensitized mice (15, 17), suggesting that IL-22 plays a protective role against airway inflammation in the challenge phase. Regarding the underlying mechanism, we found that IL-22 inhibits the expression of epithelial cytokines that play a key role in the induction of allergic inflammation (15, 16) (Fig. 1A). Moreover, we found that the inhibitory effect of IL-22 is partly mediated by epithelial production of Reg3γ (16), a molecule known as an anti-microbial protein (44). Namely, in the search for genes regulated by IL-22, we identified Reg3γ as one of IL-22-inducible genes in lung epithelial cells, and found that the administration of recombinant Reg3γ inhibits the expression of IL-33 and TSLP in the lung and attenuates eosinophilic inflammation in allergen-challenged mice (16). On the other hand, by using hydrodynamic-based gene delivery, Nakagome et al. have revealed that enforced IL-22 expression induces IL-10 production in splenic CD4+ T cells (19). They also demonstrated that enforced IL-22 expression inhibits antigen-induced allergic airway inflammation in wild-type mice but not in IL-10-deficient mice (19). These findings suggest that IL-22 inhibits allergic airway inflammation by inducing IL-10 production from CD4+ T cells. However, the mechanisms underlying IL-22-induced IL-10 production by CD4+ cells remain unclear, since IL-22 seems to exhibit no direct effect on hematopoietic cells including CD4+ cells. Another possible mechanism underlying the protective effect of IL-22 against the development of allergic airway inflammation is related to its effect on epithelial barrier function. It has recently been shown that IL-22 plays a critical role in the maintenance of the intestinal epithelial barrier after injury by promoting epithelial stem cell expansion (45, 46). Since lung epithelial cells also contain several kinds of stem cells (47), it is possible that IL-22 maintains epithelial barrier function in the lung by promoting epithelial regeneration (Fig. 1B). Moreover, recent studies have raised another possibility that IL-22 indirectly affects the pathogenesis of asthma. It has been shown that bacterial colonization in the intestine is affected by IL-22 through the production of anti-microbacterial proteins (48, 49) (Fig. 1C). It has also been shown that the gut microbiota is associated with the pathogenesis of asthma (50). These findings suggest that IL-22 may affect the pathogenesis of asthma through its effect on the gut microbiota. It is also possible that IL-22 may affect the pathogenesis of asthma by altering lung microbiota. These possibilities should be explored in future. Interestingly, IL-22 has recently been demonstrated to have an ability to alleviate diet-induced obesity, insulin resistance and metabolic disorders in mice (51). Because it is well known that obesity increases both the onset and the severity of asthma (52), and because a recent clinical study has shown that insulin resistance and metabolic diseases are associated with the aggravation of lung function in patients with asthma (53), IL-22 may improve the phenotype of asthma by attenuating metabolic abnormalities (Fig. 1C). Taken together, these findings suggest that IL-22 has protective roles in allergic airway inflammation by several distinct mechanisms. Airway hyperresponsiveness to a variety of bronchoconstricting agents is another pathophysiological feature of asthma. We have shown that airway hyperresponsiveness is enhanced in IL-22-deficient mice or by the neutralization of IL-22 (15, 16). In this regard, Kudo et al. have shown that IL-17A but not IL-22 enhances contraction force generation of airway smooth muscle (54). These findings suggest that the enhanced airway hyperresponsiveness in the absence of IL-22 seems to be dependent on the exaggerated airway inflammation in the absence of IL-22 rather than the direct effect of IL-22 on smooth muscle. Pathogenic roles of IL-22 in allergic airway inflammation in mice In contrast to its protective roles in allergen-induced allergic inflammation, pro-inflammatory roles of IL-22 have been reported in fungus-induced allergic inflammation in mice (21). Using a chronic fungus inhalation model in mice, Lilly et al. have shown that IL-22 is expressed in the lung together with IL-17A and that IL-22 deficiency results in attenuated expression of pro-inflammatory cytokines/chemokines such as IL-33, IL-1β, CCL17 and CXCL1 and thus in improved airway hyperresponsiveness (21). In this regard, it has been shown that IL-22 exhibits pro-inflammatory properties, especially if IL-22 is released together with other inflammatory cytokines such as IL-17A, in bleomycin-induced airway inflammation in mice (55). Thus, IL-22 may enhance fungus-induced allergic inflammation in lung, because there are a number of Th17 cells that produce pro-inflammatory cytokines including IL-17A and IL-17F in this model. Roles of IL-22 in allergen sensitization in mice In the majority of patients with asthma, it is largely unknown how they are sensitized by environmental allergens. As atopic dermatitis often precedes the development of asthma, it is generally considered that allergen sensitization through injured skin is crucial for the onset of asthma (56). In this regard, in contrast to the protective role of IL-22 during the challenge phase of allergic airway inflammation, a series of studies has revealed a pro-inflammatory role of IL-22 in atopic dermatitis and in allergen sensitization through the skin (17, 57, 58). Besnard et al. have shown that mice injected with a neutralizing antibody against IL-22 during the subcutaneous allergen sensitization period develop significantly attenuated airway inflammation upon inhaled allergen challenge (17). In addition, recent studies have shown that epicutaneous allergen exposure induces IL-22-producing CD4+ T cells, which is essential for the development of atopic dermatitis-like skin lesions and systemic Th2-type immune responses (57, 58). Taken together, these findings indicate that IL-22 promotes allergen sensitization occurring in the skin but inhibits the development of allergic inflammation in the airways. Further studies are needed to clarify the physiological meaning of these conflicting functions of IL-22 in the sensitization phase and the inflammation phase in asthma. Roles of IL-22 in patients with asthma A previous study showing that serum levels of IL-22 are increased in patients with asthma as compared with healthy volunteers (17) suggests the possible involvement of IL-22 in the pathogenesis of asthma. Consistent with our data in murine asthma models, a recent study investigating the cellular source of IL-22 in patients with asthma has shown that the majority of IL-22-producing cells in the lung are CD4+ T cells (20). Among the IL-22-producing CD4+ T cells in the lung of asthmatic patients, the most frequent population is CD4+ T cells that co-produce IFN-γ and are designated as Th1/IL-22+ cells (20). On the other hand, a small population of IL-22-producing CD4+ T cells co-produces IL-17, suggesting that IL-22 is weakly associated with Th17 cells in patients with asthma (20). So far, there have been few studies exploring the mechanisms by which IL-22 regulates the pathophysiology of asthma in humans. Pennino et al. have shown that IL-22 inhibits IFN-γ-induced secretion of pro-inflammatory chemokines such as CCL5 and CXCL10 from human lung epithelial cells (20). Because IFN-γ is capable of eliciting inflammatory cytokine expression and has recently been implicated in the pathogenesis of severe asthma (59, 60), it is possible that IL-22 exhibits an inhibitory effect on airway inflammation in asthma by inhibiting the effect of IFN-γ on epithelial cells. On the other hand, it remains unclear whether IL-22 has a role in allergen sensitization and airway hyperresponsiveness in patients with asthma. IL-22 binding protein: a negative regulator of IL-22 Because IL-22 plays critical roles in barrier function in the epithelium and the dysregulation of IL-22 action leads to the deleterious inflammation and the development of diseases such as atopic dermatitis and psoriasis, IL-22 function should be tightly controlled for the maintenance of epithelial homeostasis. One candidate molecule that seems to be involved in the control of IL-22 action is IL-22-binding protein (IL-22BP), a soluble receptor for IL-22, which shows high homology to IL-22R1 and exhibits a much higher binding affinity than transmembrane IL-22R does (61, 62). Consistently, in vitro experiments showed that IL-22BP is capable of inhibiting IL-22-induced gene expression by neutralizing IL-22 activity (61). The role of IL-22BP as an endogenous inhibitor of IL-22 is further confirmed by an in vivo study demonstrating that colitis-associated tumor development is accelerated in IL-22BP-deficient mice (63). Moreover, regulatory roles of IL-22BP in the lung were confirmed in pneumonia models in mice (64). In contrast to IL-22, which mainly functions in mucosal tissues, IL-22BP is highly expressed in secondary lymphoid organs, such as spleen and lymph nodes (65). Importantly, whereas IL-22BP is constitutively expressed by conventional DCs in steady-state conditions, its expression is down-regulated in inflammatory conditions, thereby resulting in an increase in IL-22 bioactivity (63). Interestingly, recent studies have shown that CD4+ T cells (66) and eosinophils (67) play a pathogenic role in inflammatory bowel diseases by antagonizing the protective function of IL-22 via the expression of IL-22BP. Although little evidence exists, it is possible that IL-22BP produced by DCs, CD4+ T cells or eosinophils functions as an endogenous inhibitor of IL-22 function in the development of asthma. Concluding remarks Not only murine studies but also clinical studies of patients with asthma suggest the involvement of IL-22 in the pathogenesis of asthma. Among a variety of IL-22 functions, the effect on epithelial cells to regenerate and repair its barrier function seems to be most prominent. This effect makes IL-22 an attractive candidate for a novel therapy against asthma. However, depending on the context and/or the environmental milieu, IL-22 may be causatively involved in asthma. Since it is well appreciated that asthma is a heterogeneous disease that is composed of several endotypes and phenotypes (68–70), therapeutic strategy should be individualized or endotype-based. In some endotypes of asthma, the goal seems to be the induction of IL-22, whereas the suppression of IL-22 function may be applicable to other endotypes of asthma. Further research into the molecular mechanisms of IL-22 action and into the precise roles of IL-22 in asthma pathogenesis in each phenotype/endotype are needed to achieve successful clinical translation of these therapeutic strategies. Funding This work was supported in part by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of the Japanese Government, Japan. Conflicts of interest statement: the authors have no financial interest to disclose. References 1 GBD 2015 Healthcare Access and Quality Collaborators . 2017 . Healthcare access and quality index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the global burden of disease study 2015 . Lancet 390 : 231 . CrossRef Search ADS PubMed 2 Fahy , J. V . 2015 . Type 2 inflammation in asthma—present in most, absent in many . Nat. Rev. Immunol . 15 : 57 . 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International Immunology – Oxford University Press
Published: Jan 31, 2018
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