IL-25 (IL-17E) in epithelial immunology and pathophysiology

IL-25, also known as IL-17E, is a unique cytokine of the IL-17 family. Indeed, IL-25 exclusively was shown to strongly induce expression of the cytokines associated with type 2 immunity. Although produced by several types of immune cells, such as T cells, dendritic cells, or group 2 innate lymphoid cells, a vast amount of IL-25 derives from epithelial cells. The functions of IL-25 have been actively studied in the context of physiology and pathology of various organs including skin, airways and lungs, gastrointestinal tract, and thymus. Accumulating evidence suggests that IL-25 is a “barrier surface” cytokine whose expression depends on extrinsic environmental factors and when upregulated may lead to inflammatory disorders such as atopic dermatitis, psoriasis, or asthma. This review summarizes the progress of the recent years regarding the effects of IL-25 on the regulation of immune response and the balance between its homeostatic and pathogenic role in various epithelia. We revisit IL-25’s general and tissue-specific mechanisms of action, mediated signaling pathways, and transcription factors activated in immune and resident cells. Finally, we discuss perspectives of the IL-25–based therapies for inflammatory disorders and compare them with the mainstream ones that target IL-17A. IL-25, also known as IL-17E, is a unique cytokine of the IL-17 family. Indeed, IL-25 exclusively was shown to strongly induce expression of the cytokines associated with type 2 immunity. Although produced by several types of immune cells, such as T cells, dendritic cells, or group 2 innate lymphoid cells, a vast amount of IL-25 derives from epithelial cells. The functions of IL-25 have been actively studied in the context of physiology and pathology of various organs including skin, airways and lungs, gastrointestinal tract, and thymus. Accumulating evidence suggests that IL-25 is a “barrier surface” cytokine whose expression depends on extrinsic environmental factors and when upregulated may lead to inflammatory disorders such as atopic dermatitis, psoriasis, or asthma. This review summarizes the progress of the recent years regarding the effects of IL-25 on the regulation of immune response and the balance between its homeostatic and pathogenic role in various epithelia. We revisit IL-25’s general and tissue-specific mechanisms of action, mediated signaling pathways, and transcription factors activated in immune and resident cells. Finally, we discuss perspectives of the IL-25–based therapies for inflammatory disorders and compare them with the mainstream ones that target IL-17A. Epithelia at mucosal and cutaneous surfaces form the protective barriers against various assaults from the external environment. It is now clear that except for mechanical protection, epithelia evolved as complex tissues that play an important role in sensing and integrating environmental cues.1Roan F. Obata-Ninomiya K. Ziegler S.F. Epithelial cell-derived cytokines: more than just signaling the alarm.J Clin Invest. 2019; 129: 1441-1451Crossref PubMed Scopus (80) Google Scholar Emerging evidence points to IL-25 (also known as IL-17E) as an intriguing “barrier cytokine” that participates in maintaining homeostasis, tissue adaption to external damages, alarming the immune cells, and stimulating the repair in case of injury. First identified in 2001, IL-25 maps to chromosome 14q11 and belongs to the IL-17 family of cytokines (comprising 6 members: IL-17A, IL-17B, IL-17C, IL-17D, IL-25, and IL-17F). Nevertheless, it shares only 16% homology with IL-17A and has biological effects that largely differ from those of the other members of the family.2Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar, 3Lee J. Ho W.H. Maruoka M. Corpuz R.T. Baldwin D.T. Foster J.S. et al.IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1.J Biol Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 4Brembilla N.C. Senra L. Boehncke W.H. The IL-17 family of cytokines in psoriasis: IL-17A and beyond.Front Immunol. 2018; 9: 1682Crossref PubMed Scopus (115) Google Scholar IL-17A is expressed by TH17 cells, whereas IL-25 was originally described by Fort et al2Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar as a TH2-produced cytokine implicated in the induction of TH2-like responses.2Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar Indeed, infusion of mice with IL-25 induces the expression of cytokines such as IL-4, IL-5, and IL-13, and leads to increase serum IgE levels, blood eosinophilia, and pathological changes in the lungs and digestive tract characterized by increased mucus production and epithelial cell hyperplasia.2Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar In addition to TH2 cells, IL-25 was later shown to be produced by various immune cells such as CD8+ T cells, mast cells, macrophages, dendritic cells (DCs), eosinophils, basophils, and group 2 innate lymphoid cells (ILC2s).1Roan F. Obata-Ninomiya K. Ziegler S.F. Epithelial cell-derived cytokines: more than just signaling the alarm.J Clin Invest. 2019; 129: 1441-1451Crossref PubMed Scopus (80) Google Scholar,5Owyang A.M. Zaph C. Wilson E.H. Guild K.J. McClanahan T. Miller H.R.P. et al.Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract.J Exp Med. 2006; 203: 843-849Crossref PubMed Scopus (273) Google Scholar, 6Angkasekwinai P. Park H. Wang Y.H. Wang Y.H. Chang S.H. 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Specifically, the epithelium-derived IL-25 has been demonstrated to play major roles in homeostasis and pathologies of various organs. The IL-25 receptor–expressing cells are found in most organs including skin, kidney, pancreas, liver, brain, and intestine.10Kolls J.K. Lindén A. Interleukin-17 family members and inflammation.Immunity. 2004; 21: 467-476Abstract Full Text Full Text PDF PubMed Scopus (1856) Google Scholar Cellular targets of IL-25 include T cells, ILC2s, specific myeloid populations, and invariant natural killer T (iNKT) cells, as well as nonhematopoietic-cell populations such as fibroblasts, epithelial cells, endothelial cells, and mesenchymal cells.2Fort M.M. Cheung J. Yen D. Li J. Zurawski S.M. Lo S. et al.IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo.Immunity. 2001; 15: 985-995Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar,6Angkasekwinai P. Park H. Wang Y.H. Wang Y.H. Chang S.H. 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Swart D.A. et al.Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.J Immunol. 2008; 181: 4299-4310Crossref PubMed Google Scholar modulation of cell-cell adhesion,25Cheung P.F. Wong C.K. Ip W.K. Lam C.W. IL-25 regulates the expression of adhesion molecules on eosinophils: mechanism of eosinophilia in allergic inflammation.Allergy. 2006; 61: 878-885Crossref PubMed Scopus (66) Google Scholar,26Sonobe Y. Takeuchi H. Kataoka K. Li H. Jin S. Mimuro M. et al.Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cepsilon-dependent manner.J Biol Chem. 2009; 284: 31834-31842Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and cell motility.21Borowczyk J. Buerger C. Tadjrischi N. Drukala J. Wolnicki M. Wnuk D. et al.IL-17E (IL-25) and IL-17A differentially affect the functions of human keratinocytes.J Invest Dermatol. 2020; 140: 1379-1389.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In this review, we summarize the current knowledge regarding the principles of IL-25 signaling. Subsequently, we provide an overview of the regulation and functions of IL-25 in the physiology and pathology of skin, gut, and airway epithelia. Next, we give an overview of the recent discoveries regarding IL-25 in the thymus. Finally, the perspectives of the use of IL-25 as a therapeutic target are discussed. IL-25, as other IL-17 family members, is secreted from the cell in the form of disulphide-linked dimers. The binding receptor for IL-25, IL-17RB, requires association with IL-17RA to form a complex to mediate downstream signaling cascades in the target cells.7Xu M. Dong C. IL-25 in allergic inflammation.Immunol Rev. 2017; 278: 185-191Crossref PubMed Scopus (41) Google Scholar In vitro, IL-17RA binds to the IL-17RB-IL-25 complex rather than directly to IL-25.27Ely L.K. Fischer S. Garcia K.C. Structural basis of receptor sharing by interleukin 17 cytokines.Nat Immunol. 2009; 10: 1245-1251Crossref PubMed Scopus (137) Google Scholar Both receptor subunits are, however, required for an efficient signaling, because mice deficient for IL17RA or IL-17RB fail to respond to IL-25.16Saenz S.A. Siracusa M.C. Perrigoue J.G. Spencer S.P. Urban Jr., J.F. Tocker J.E. et al.IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.Nature. 2010; 464: 1362-1366Crossref PubMed Scopus (440) Google Scholar,23Hymowitz S.G. Filvaroff E.H. Yin J.P. Lee J. Cai L. 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Foster J.S. et al.IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1.J Biol Chem. 2001; 276: 1660-1664Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar,9Iwakura Y. Ishigame H. Saijo S. Nakae S. Functional specialization of interleukin-17 family members.Immunity. 2011; 34: 149-162Abstract Full Text Full Text PDF PubMed Scopus (828) Google Scholar,32Chang S.H. Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation.Cell Signal. 2011; 23: 1069-1075Crossref PubMed Scopus (145) Google Scholar In line with this, IL-17B and IL-25 were found to act as antagonists in mouse models of acute colonic inflammation, Citrobacter rodentium infection, and allergic asthma.31Reynolds J.M. Lee Y.H. Shi Y. Wang X. Angkasekwinai P. 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Erzurum S. et al.TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.J Immunol. 2015; 194: 2826-2837Crossref PubMed Scopus (0) Google Scholar TRAF4 also has been shown to mediate Act1-dependent signaling events downstream of IL-25 receptor.48Zepp J.A. Wu L. Qian W. Ouyang W. Aronica M. Erzurum S. et al.TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.J Immunol. 2015; 194: 2826-2837Crossref PubMed Scopus (0) Google Scholar TRAF4 activates the E3 ligase smadubiquitin regulatory factor 2, which leads to the ubiquitylation and subsequent degradation of the inhibitory protein DAZAP2 (deleted in azoospermia DAZ-associated protein 2),48Zepp J.A. Wu L. Qian W. Ouyang W. Aronica M. 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Erzurum S. et al.TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.J Immunol. 2015; 194: 2826-2837Crossref PubMed Scopus (0) Google Scholar Of interest, primary T cells and epithelial cells derived from these mice showed abolished IL-25–induced phosphorylation of ERK1/2 and P38, revealing that activation of MAPKs might be somehow dependent on TRAF4. STAT5 is also recruited to the IL-25 receptor in a TRAF4-dependent and Act1-independent manner, via direct interaction with unique tyrosine residues Y444 and Y454 on IL-17RB.41Swaidani S. Bulek K. Kang Z. Liu C. Lu Y. Yin W. et al.The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation.J Immunol. 2009; 182: 1631-1640Crossref PubMed Google Scholar,50Wu H.H. Hwang-Verslues W.W. Lee W.H. Huang C.K. Wei P.C. 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