Roles of IL-22 in allergic airway inflammation in mice and humans

Roles of IL-22 in allergic airway inflammation in mice and humans 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. Google Scholar CrossRef Search ADS PubMed  3 Robinson, D. S., Hamid, Q., Ying, S.et al.   1992. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med . 326: 298. Google Scholar CrossRef Search ADS PubMed  4 Humbert, M., Durham, S. R., Ying, S.et al.   1996. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against ‘intrinsic’ asthma being a distinct immunopathologic entity. Am. J. Respir. Crit. Care Med . 154: 1497. Google Scholar CrossRef Search ADS PubMed  5 Foster, P. S., Hogan, S. P., Ramsay, A. J., Matthaei, K. I. and Young, I. G. 1996. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med . 183: 195. Google Scholar CrossRef Search ADS PubMed  6 Wills-Karp, M., Luyimbazi, J., Xu, X.et al.   1998. Interleukin-13: central mediator of allergic asthma. Science  282: 2258. Google Scholar CrossRef Search ADS PubMed  7 Grünig, G., Warnock, M., Wakil, A. E.et al.   1998. Requirement for IL-13 independently of IL-4 in experimental asthma. Science  282: 2261. Google Scholar CrossRef Search ADS PubMed  8 Chung, K. F. 2015. Targeting the interleukin pathway in the treatment of asthma. Lancet  386: 1086. Google Scholar CrossRef Search ADS PubMed  9 van Rijt, L. S., Jung, S., Kleinjan, A.et al.   2005. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med . 201: 981. Google Scholar CrossRef Search ADS PubMed  10 Plantinga, M., Guilliams, M., Vanheerswynghels, M.et al.   2013. Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity  38: 322. Google Scholar CrossRef Search ADS PubMed  11 Hammad, H. and Lambrecht, B. N. 2015. Barrier epithelial cells and the control of type 2 immunity. Immunity  43: 29. Google Scholar CrossRef Search ADS PubMed  12 Yu, S., Kim, H. Y., Chang, Y. J., DeKruyff, R. H. and Umetsu, D. T. 2014. Innate lymphoid cells and asthma. J. Allergy Clin. Immunol . 133: 943. Google Scholar CrossRef Search ADS PubMed  13 Lambrecht, B. N. and Hammad, H. 2014. Allergens and the airway epithelium response: gateway to allergic sensitization. J. Allergy Clin. Immunol . 134: 499. Google Scholar CrossRef Search ADS PubMed  14 Dudakov, J. A., Hanash, A. M. and van den Brink, M. R. 2015. Interleukin-22: immunobiology and pathology. Annu. Rev. Immunol . 33: 747. Google Scholar CrossRef Search ADS PubMed  15 Takahashi, K., Hirose, K., Kawashima, S.et al.   2011. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J. Allergy Clin. Immunol . 128: 1067. Google Scholar CrossRef Search ADS PubMed  16 Ito, T., Hirose, K., Saku, A.et al.   2017. IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite-induced asthma models. J. Exp. Med . 214: 3037. Google Scholar CrossRef Search ADS PubMed  17 Besnard, A. G., Sabat, R., Dumoutier, L.et al.   2011. Dual role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am. J. Respir. Crit. Care Med . 183: 1153. Google Scholar CrossRef Search ADS PubMed  18 Taube, C., Tertilt, C., Gyülveszi, G.et al.   2011. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLoS One  6: e21799. Google Scholar CrossRef Search ADS PubMed  19 Nakagome, K., Imamura, M., Kawahata, K.et al.   2011. High expression of IL-22 suppresses antigen-induced immune responses and eosinophilic airway inflammation via an IL-10-associated mechanism. J. Immunol . 187: 5077. Google Scholar CrossRef Search ADS PubMed  20 Pennino, D., Bhavsar, P. K., Effner, R.et al.   2013. IL-22 suppresses IFN-γ-mediated lung inflammation in asthmatic patients. J. Allergy Clin. Immunol . 131: 562. Google Scholar CrossRef Search ADS PubMed  21 Lilly, L. M., Gessner, M. A., Dunaway, C. W.et al.   2012. The β-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22. J. Immunol . 189: 3653. Google Scholar CrossRef Search ADS PubMed  22 Dumoutier, L., Louahed, J. and Renauld, J. C. 2000. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J. Immunol . 164: 1814. Google Scholar CrossRef Search ADS PubMed  23 Dumoutier, L., Van Roost, E., Ameye, G., Michaux, L. and Renauld, J. C. 2000. IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun . 1: 488. Google Scholar CrossRef Search ADS PubMed  24 Sabat, R., Ouyang, W. and Wolk, K. 2014. Therapeutic opportunities of the IL-22-IL-22R1 system. Nat. Rev. Drug Discov . 13: 21. Google Scholar CrossRef Search ADS PubMed  25 Dumoutier, L., Van Roost, E., Colau, D. and Renauld, J. C. 2000. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc. Natl Acad. Sci. USA  97: 10144. Google Scholar CrossRef Search ADS   26 Xie, M. H., Aggarwal, S., Ho, W. H.et al.   2000. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem . 275: 31335. Google Scholar CrossRef Search ADS PubMed  27 Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V., Esterova, E., Dickensheets, H., Donnelly, R. P. and Pestka, S. 2001. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol. Chem . 276: 2725. Google Scholar CrossRef Search ADS PubMed  28 Lejeune, D., Dumoutier, L., Constantinescu, S., Kruijer, W., Schuringa, J. J. and Renauld, J. C. 2002. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. pathways that are shared with and distinct from IL-10. J. Biol. Chem . 277: 33676. Google Scholar CrossRef Search ADS PubMed  29 Wolk, K., Kunz, S., Witte, E., Friedrich, M., Asadullah, K. and Sabat, R. 2004. IL-22 increases the innate immunity of tissues. Immunity  21: 241. Google Scholar CrossRef Search ADS PubMed  30 Wilson, N. J., Boniface, K., Chan, J. R.et al.   2007. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat. Immunol . 8: 950. Google Scholar CrossRef Search ADS PubMed  31 Liang, S. C., Tan, X. Y., Luxenberg, D. P., Karim, R., Dunussi-Joannopoulos, K., Collins, M. and Fouser, L. A. 2006. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med . 203: 227. Google Scholar CrossRef Search ADS PubMed  32 Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. and Sallusto, F. 2009. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol . 10: 857. Google Scholar CrossRef Search ADS PubMed  33 Hamada, H., Garcia-Hernandez Mde, L., Reome, J. B.et al.   2009. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J. Immunol . 182: 3469. Google Scholar CrossRef Search ADS PubMed  34 Martin, B., Hirota, K., Cua, D. J., Stockinger, B. and Veldhoen, M. 2009. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity  31: 321. Google Scholar CrossRef Search ADS PubMed  35 Sutton, C. E., Lalor, S. J., Sweeney, C. M., Brereton, C. F., Lavelle, E. C. and Mills, K. H. 2009. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity  31: 331. Google Scholar CrossRef Search ADS PubMed  36 Simonian, P. L., Wehrmann, F., Roark, C. L., Born, W. K., O’Brien, R. L. and Fontenot, A. P. 2010. γδ T cells protect against lung fibrosis via IL-22. J. Exp. Med . 207: 2239. Google Scholar CrossRef Search ADS PubMed  37 Spits, H., Artis, D., Colonna, M.et al.   2013. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol . 13: 145. Google Scholar CrossRef Search ADS PubMed  38 Cella, M., Fuchs, A., Vermi, W.et al.   2009. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature  457: 722. Google Scholar CrossRef Search ADS PubMed  39 Cella, M., Otero, K. and Colonna, M. 2010. Expansion of human NK-22 cells with IL-7, IL-2, and IL-1beta reveals intrinsic functional plasticity. Proc. Natl Acad. Sci. USA  107: 10961. Google Scholar CrossRef Search ADS   40 Colonna, M. 2009. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity  31: 15. Google Scholar CrossRef Search ADS PubMed  41 Satoh-Takayama, N., Lesjean-Pottier, S., Vieira, P.et al.   2010. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med . 207: 273. Google Scholar CrossRef Search ADS PubMed  42 Basu, R., O’Quinn, D. B., Silberger, D. J.et al.   2012. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity  37: 1061. Google Scholar CrossRef Search ADS PubMed  43 Paget, C., Ivanov, S., Fontaine, J.et al.   2012. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J. Biol. Chem . 287: 8816. Google Scholar CrossRef Search ADS PubMed  44 Loonen, L. M., Stolte, E. H., Jaklofsky, M. T.et al.   2014. REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol . 7: 939. Google Scholar CrossRef Search ADS PubMed  45 Lindemans, C. A., Calafiore, M., Mertelsmann, A. M.et al.   2015. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature  528: 560. Google Scholar CrossRef Search ADS PubMed  46 Hanash, A. M., Dudakov, J. A., Hua, G.et al.   2012. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity  37: 339. Google Scholar CrossRef Search ADS PubMed  47 Rock, J. R. and Hogan, B. L. 2011. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu. Rev. Cell Dev. Biol . 27: 493. Google Scholar CrossRef Search ADS PubMed  48 Zenewicz, L. A., Yin, X., Wang, G.et al.   2013. IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J. Immunol . 190: 5306. Google Scholar CrossRef Search ADS PubMed  49 Behnsen, J., Jellbauer, S., Wong, C. P.et al.   2014. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity  40: 262. Google Scholar CrossRef Search ADS PubMed  50 Huang, Y. J. and Boushey, H. A. 2015. The microbiome in asthma. J. Allergy Clin. Immunol . 135: 25. Google Scholar CrossRef Search ADS PubMed  51 Wang, X., Ota, N., Manzanillo, P.et al.   2014. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature  514: 237. Google Scholar CrossRef Search ADS PubMed  52 Mosen, D. M., Schatz, M., Magid, D. J. and Camargo, C. A. Jr. 2008. The relationship between obesity and asthma severity and control in adults. J. Allergy Clin. Immunol . 122: 507. Google Scholar CrossRef Search ADS PubMed  53 Forno, E., Han, Y. Y., Muzumdar, R. H. and Celedón, J. C. 2015. Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. J. Allergy Clin. Immunol . 136: 304. Google Scholar CrossRef Search ADS PubMed  54 Kudo, M., Melton, A. C., Chen, C.et al.   2012. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med . 18: 547. Google Scholar CrossRef Search ADS PubMed  55 Sonnenberg, G. F., Nair, M. G., Kirn, T. J., Zaph, C., Fouser, L. A. and Artis, D. 2010. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med . 207: 1293. Google Scholar CrossRef Search ADS PubMed  56 Dharmage, S. C., Lowe, A. J., Matheson, M. C., Burgess, J. A., Allen, K. J. and Abramson, M. J. 2014. Atopic dermatitis and the atopic march revisited. Allergy  69: 17. Google Scholar CrossRef Search ADS PubMed  57 Lou, H., Lu, J., Choi, E. B.et al.   2017. Expression of IL-22 in the skin causes Th2-biased immunity, epidermal barrier dysfunction, and pruritus via stimulating epithelial Th2 cytokines and the GRP Pathway. J. Immunol . 198: 2543. Google Scholar CrossRef Search ADS PubMed  58 Glocova, I., Brück, J., Geisel, J.et al.   2017. Induction of skin-pathogenic Th22 cells by epicutaneous allergen exposure. J. Dermatol. Sci . 87: 268. Google Scholar CrossRef Search ADS PubMed  59 Raundhal, M., Morse, C., Khare, A.et al.   2015. High IFN-γ and low SLPI mark severe asthma in mice and humans. J. Clin. Invest . 125: 3037. Google Scholar CrossRef Search ADS PubMed  60 Ray, A., Raundhal, M., Oriss, T. B., Ray, P. and Wenzel, S. E. 2016. Current concepts of severe asthma. J. Clin. Invest . 126: 2394. Google Scholar CrossRef Search ADS PubMed  61 Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V.et al.   2001. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol . 166: 7096. Google Scholar CrossRef Search ADS PubMed  62 Wolk, K., Witte, E., Hoffmann, U.et al.   2007. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s disease. J. Immunol . 178: 5973. Google Scholar CrossRef Search ADS PubMed  63 Huber, S., Gagliani, N., Zenewicz, L. A.et al.   2012. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature  491: 259. Google Scholar CrossRef Search ADS PubMed  64 Broquet, A., Jacqueline, C., Davieau, M.et al.   2017. Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model. Sci. Rep . 7: 11010. Google Scholar CrossRef Search ADS PubMed  65 Martin, J. C., Bériou, G., Heslan, M.et al.   2014. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol . 7: 101. Google Scholar CrossRef Search ADS PubMed  66 Pelczar, P., Witkowski, M., Perez, L. G.et al.   2016. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science  354: 358. Google Scholar CrossRef Search ADS PubMed  67 Martin, J. C., Bériou, G., Heslan, M.et al.   2016. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol . 9: 539. Google Scholar CrossRef Search ADS PubMed  68 Haldar, P., Pavord, I. D., Shaw, D. E.et al.   2008. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med . 178: 218. Google Scholar CrossRef Search ADS PubMed  69 Amelink, M., de Nijs, S. B., de Groot, J. C.et al.   2013. Three phenotypes of adult-onset asthma. Allergy  68: 674. Google Scholar CrossRef Search ADS PubMed  70 Wu, W., Bleecker, E., Moore, W.et al.   2014. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J. Allergy Clin. Immunol . 133: 1280. Google Scholar CrossRef Search ADS PubMed  © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

Roles of IL-22 in allergic airway inflammation in mice and humans

Loading next page...
 
/lp/ou_press/roles-of-il-22-in-allergic-airway-inflammation-in-mice-and-humans-JMHAeTryvp
Publisher
Oxford University Press
Copyright
© The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
ISSN
0953-8178
eISSN
1460-2377
D.O.I.
10.1093/intimm/dxy010
Publisher site
See Article on Publisher Site

Abstract

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. Google Scholar CrossRef Search ADS PubMed  3 Robinson, D. S., Hamid, Q., Ying, S.et al.   1992. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med . 326: 298. Google Scholar CrossRef Search ADS PubMed  4 Humbert, M., Durham, S. R., Ying, S.et al.   1996. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against ‘intrinsic’ asthma being a distinct immunopathologic entity. Am. J. Respir. Crit. Care Med . 154: 1497. Google Scholar CrossRef Search ADS PubMed  5 Foster, P. S., Hogan, S. P., Ramsay, A. J., Matthaei, K. I. and Young, I. G. 1996. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med . 183: 195. Google Scholar CrossRef Search ADS PubMed  6 Wills-Karp, M., Luyimbazi, J., Xu, X.et al.   1998. Interleukin-13: central mediator of allergic asthma. Science  282: 2258. Google Scholar CrossRef Search ADS PubMed  7 Grünig, G., Warnock, M., Wakil, A. E.et al.   1998. Requirement for IL-13 independently of IL-4 in experimental asthma. Science  282: 2261. Google Scholar CrossRef Search ADS PubMed  8 Chung, K. F. 2015. Targeting the interleukin pathway in the treatment of asthma. Lancet  386: 1086. Google Scholar CrossRef Search ADS PubMed  9 van Rijt, L. S., Jung, S., Kleinjan, A.et al.   2005. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med . 201: 981. Google Scholar CrossRef Search ADS PubMed  10 Plantinga, M., Guilliams, M., Vanheerswynghels, M.et al.   2013. Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity  38: 322. Google Scholar CrossRef Search ADS PubMed  11 Hammad, H. and Lambrecht, B. N. 2015. Barrier epithelial cells and the control of type 2 immunity. Immunity  43: 29. Google Scholar CrossRef Search ADS PubMed  12 Yu, S., Kim, H. Y., Chang, Y. J., DeKruyff, R. H. and Umetsu, D. T. 2014. Innate lymphoid cells and asthma. J. Allergy Clin. Immunol . 133: 943. Google Scholar CrossRef Search ADS PubMed  13 Lambrecht, B. N. and Hammad, H. 2014. Allergens and the airway epithelium response: gateway to allergic sensitization. J. Allergy Clin. Immunol . 134: 499. Google Scholar CrossRef Search ADS PubMed  14 Dudakov, J. A., Hanash, A. M. and van den Brink, M. R. 2015. Interleukin-22: immunobiology and pathology. Annu. Rev. Immunol . 33: 747. Google Scholar CrossRef Search ADS PubMed  15 Takahashi, K., Hirose, K., Kawashima, S.et al.   2011. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J. Allergy Clin. Immunol . 128: 1067. Google Scholar CrossRef Search ADS PubMed  16 Ito, T., Hirose, K., Saku, A.et al.   2017. IL-22 induces Reg3γ and inhibits allergic inflammation in house dust mite-induced asthma models. J. Exp. Med . 214: 3037. Google Scholar CrossRef Search ADS PubMed  17 Besnard, A. G., Sabat, R., Dumoutier, L.et al.   2011. Dual role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am. J. Respir. Crit. Care Med . 183: 1153. Google Scholar CrossRef Search ADS PubMed  18 Taube, C., Tertilt, C., Gyülveszi, G.et al.   2011. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLoS One  6: e21799. Google Scholar CrossRef Search ADS PubMed  19 Nakagome, K., Imamura, M., Kawahata, K.et al.   2011. High expression of IL-22 suppresses antigen-induced immune responses and eosinophilic airway inflammation via an IL-10-associated mechanism. J. Immunol . 187: 5077. Google Scholar CrossRef Search ADS PubMed  20 Pennino, D., Bhavsar, P. K., Effner, R.et al.   2013. IL-22 suppresses IFN-γ-mediated lung inflammation in asthmatic patients. J. Allergy Clin. Immunol . 131: 562. Google Scholar CrossRef Search ADS PubMed  21 Lilly, L. M., Gessner, M. A., Dunaway, C. W.et al.   2012. The β-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22. J. Immunol . 189: 3653. Google Scholar CrossRef Search ADS PubMed  22 Dumoutier, L., Louahed, J. and Renauld, J. C. 2000. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J. Immunol . 164: 1814. Google Scholar CrossRef Search ADS PubMed  23 Dumoutier, L., Van Roost, E., Ameye, G., Michaux, L. and Renauld, J. C. 2000. IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun . 1: 488. Google Scholar CrossRef Search ADS PubMed  24 Sabat, R., Ouyang, W. and Wolk, K. 2014. Therapeutic opportunities of the IL-22-IL-22R1 system. Nat. Rev. Drug Discov . 13: 21. Google Scholar CrossRef Search ADS PubMed  25 Dumoutier, L., Van Roost, E., Colau, D. and Renauld, J. C. 2000. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc. Natl Acad. Sci. USA  97: 10144. Google Scholar CrossRef Search ADS   26 Xie, M. H., Aggarwal, S., Ho, W. H.et al.   2000. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem . 275: 31335. Google Scholar CrossRef Search ADS PubMed  27 Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V., Esterova, E., Dickensheets, H., Donnelly, R. P. and Pestka, S. 2001. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol. Chem . 276: 2725. Google Scholar CrossRef Search ADS PubMed  28 Lejeune, D., Dumoutier, L., Constantinescu, S., Kruijer, W., Schuringa, J. J. and Renauld, J. C. 2002. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. pathways that are shared with and distinct from IL-10. J. Biol. Chem . 277: 33676. Google Scholar CrossRef Search ADS PubMed  29 Wolk, K., Kunz, S., Witte, E., Friedrich, M., Asadullah, K. and Sabat, R. 2004. IL-22 increases the innate immunity of tissues. Immunity  21: 241. Google Scholar CrossRef Search ADS PubMed  30 Wilson, N. J., Boniface, K., Chan, J. R.et al.   2007. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat. Immunol . 8: 950. Google Scholar CrossRef Search ADS PubMed  31 Liang, S. C., Tan, X. Y., Luxenberg, D. P., Karim, R., Dunussi-Joannopoulos, K., Collins, M. and Fouser, L. A. 2006. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med . 203: 227. Google Scholar CrossRef Search ADS PubMed  32 Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. and Sallusto, F. 2009. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol . 10: 857. Google Scholar CrossRef Search ADS PubMed  33 Hamada, H., Garcia-Hernandez Mde, L., Reome, J. B.et al.   2009. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J. Immunol . 182: 3469. Google Scholar CrossRef Search ADS PubMed  34 Martin, B., Hirota, K., Cua, D. J., Stockinger, B. and Veldhoen, M. 2009. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity  31: 321. Google Scholar CrossRef Search ADS PubMed  35 Sutton, C. E., Lalor, S. J., Sweeney, C. M., Brereton, C. F., Lavelle, E. C. and Mills, K. H. 2009. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity  31: 331. Google Scholar CrossRef Search ADS PubMed  36 Simonian, P. L., Wehrmann, F., Roark, C. L., Born, W. K., O’Brien, R. L. and Fontenot, A. P. 2010. γδ T cells protect against lung fibrosis via IL-22. J. Exp. Med . 207: 2239. Google Scholar CrossRef Search ADS PubMed  37 Spits, H., Artis, D., Colonna, M.et al.   2013. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol . 13: 145. Google Scholar CrossRef Search ADS PubMed  38 Cella, M., Fuchs, A., Vermi, W.et al.   2009. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature  457: 722. Google Scholar CrossRef Search ADS PubMed  39 Cella, M., Otero, K. and Colonna, M. 2010. Expansion of human NK-22 cells with IL-7, IL-2, and IL-1beta reveals intrinsic functional plasticity. Proc. Natl Acad. Sci. USA  107: 10961. Google Scholar CrossRef Search ADS   40 Colonna, M. 2009. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity  31: 15. Google Scholar CrossRef Search ADS PubMed  41 Satoh-Takayama, N., Lesjean-Pottier, S., Vieira, P.et al.   2010. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med . 207: 273. Google Scholar CrossRef Search ADS PubMed  42 Basu, R., O’Quinn, D. B., Silberger, D. J.et al.   2012. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity  37: 1061. Google Scholar CrossRef Search ADS PubMed  43 Paget, C., Ivanov, S., Fontaine, J.et al.   2012. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J. Biol. Chem . 287: 8816. Google Scholar CrossRef Search ADS PubMed  44 Loonen, L. M., Stolte, E. H., Jaklofsky, M. T.et al.   2014. REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol . 7: 939. Google Scholar CrossRef Search ADS PubMed  45 Lindemans, C. A., Calafiore, M., Mertelsmann, A. M.et al.   2015. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature  528: 560. Google Scholar CrossRef Search ADS PubMed  46 Hanash, A. M., Dudakov, J. A., Hua, G.et al.   2012. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity  37: 339. Google Scholar CrossRef Search ADS PubMed  47 Rock, J. R. and Hogan, B. L. 2011. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu. Rev. Cell Dev. Biol . 27: 493. Google Scholar CrossRef Search ADS PubMed  48 Zenewicz, L. A., Yin, X., Wang, G.et al.   2013. IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J. Immunol . 190: 5306. Google Scholar CrossRef Search ADS PubMed  49 Behnsen, J., Jellbauer, S., Wong, C. P.et al.   2014. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity  40: 262. Google Scholar CrossRef Search ADS PubMed  50 Huang, Y. J. and Boushey, H. A. 2015. The microbiome in asthma. J. Allergy Clin. Immunol . 135: 25. Google Scholar CrossRef Search ADS PubMed  51 Wang, X., Ota, N., Manzanillo, P.et al.   2014. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature  514: 237. Google Scholar CrossRef Search ADS PubMed  52 Mosen, D. M., Schatz, M., Magid, D. J. and Camargo, C. A. Jr. 2008. The relationship between obesity and asthma severity and control in adults. J. Allergy Clin. Immunol . 122: 507. Google Scholar CrossRef Search ADS PubMed  53 Forno, E., Han, Y. Y., Muzumdar, R. H. and Celedón, J. C. 2015. Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. J. Allergy Clin. Immunol . 136: 304. Google Scholar CrossRef Search ADS PubMed  54 Kudo, M., Melton, A. C., Chen, C.et al.   2012. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med . 18: 547. Google Scholar CrossRef Search ADS PubMed  55 Sonnenberg, G. F., Nair, M. G., Kirn, T. J., Zaph, C., Fouser, L. A. and Artis, D. 2010. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med . 207: 1293. Google Scholar CrossRef Search ADS PubMed  56 Dharmage, S. C., Lowe, A. J., Matheson, M. C., Burgess, J. A., Allen, K. J. and Abramson, M. J. 2014. Atopic dermatitis and the atopic march revisited. Allergy  69: 17. Google Scholar CrossRef Search ADS PubMed  57 Lou, H., Lu, J., Choi, E. B.et al.   2017. Expression of IL-22 in the skin causes Th2-biased immunity, epidermal barrier dysfunction, and pruritus via stimulating epithelial Th2 cytokines and the GRP Pathway. J. Immunol . 198: 2543. Google Scholar CrossRef Search ADS PubMed  58 Glocova, I., Brück, J., Geisel, J.et al.   2017. Induction of skin-pathogenic Th22 cells by epicutaneous allergen exposure. J. Dermatol. Sci . 87: 268. Google Scholar CrossRef Search ADS PubMed  59 Raundhal, M., Morse, C., Khare, A.et al.   2015. High IFN-γ and low SLPI mark severe asthma in mice and humans. J. Clin. Invest . 125: 3037. Google Scholar CrossRef Search ADS PubMed  60 Ray, A., Raundhal, M., Oriss, T. B., Ray, P. and Wenzel, S. E. 2016. Current concepts of severe asthma. J. Clin. Invest . 126: 2394. Google Scholar CrossRef Search ADS PubMed  61 Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V.et al.   2001. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol . 166: 7096. Google Scholar CrossRef Search ADS PubMed  62 Wolk, K., Witte, E., Hoffmann, U.et al.   2007. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s disease. J. Immunol . 178: 5973. Google Scholar CrossRef Search ADS PubMed  63 Huber, S., Gagliani, N., Zenewicz, L. A.et al.   2012. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature  491: 259. Google Scholar CrossRef Search ADS PubMed  64 Broquet, A., Jacqueline, C., Davieau, M.et al.   2017. Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model. Sci. Rep . 7: 11010. Google Scholar CrossRef Search ADS PubMed  65 Martin, J. C., Bériou, G., Heslan, M.et al.   2014. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol . 7: 101. Google Scholar CrossRef Search ADS PubMed  66 Pelczar, P., Witkowski, M., Perez, L. G.et al.   2016. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science  354: 358. Google Scholar CrossRef Search ADS PubMed  67 Martin, J. C., Bériou, G., Heslan, M.et al.   2016. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol . 9: 539. Google Scholar CrossRef Search ADS PubMed  68 Haldar, P., Pavord, I. D., Shaw, D. E.et al.   2008. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med . 178: 218. Google Scholar CrossRef Search ADS PubMed  69 Amelink, M., de Nijs, S. B., de Groot, J. C.et al.   2013. Three phenotypes of adult-onset asthma. Allergy  68: 674. Google Scholar CrossRef Search ADS PubMed  70 Wu, W., Bleecker, E., Moore, W.et al.   2014. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J. Allergy Clin. Immunol . 133: 1280. Google Scholar CrossRef Search ADS PubMed  © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Journal

International ImmunologyOxford University Press

Published: Jan 31, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off