title: Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice.
abstract: The interleukin-23 (IL-23) pathway has emerged as a promising therapeutic target for inflammatory bowel disease. Although the pathogenic role of IL-23 receptor (IL-23R) on T lymphocytes is well established, its function on innate immune cells has not been thoroughly examined. Here we investigate the consequence of IL-23R deletion in dextran sulfate sodium (DSS)-induced colitis. In IL23R(-/-) and IL23p19(-/-) mice, we observed decreased weight loss and reduced leukocyte infiltrate following DSS exposure. Surprisingly, when the IL-23R(-/-) allele was crossed into Rag2(-/-) mice, we observed exacerbated disease, increased epithelial damage, reduced pSTAT3 in the epithelium, and delayed recovery of IL23R(-/-)Rag2(-/-) mice. This phenotype was rescued with exogenous IL22-Fc, and epithelial pSTAT3 was restored. Depletion of Thy1(+) innate lymphoid cells eliminated the majority of IL-22 production in the colon lamina propria of DSS-treated Rag2(-/-) mice, suggesting that these are the major IL-23 responsive innate cells in this context. In summary, we provide evidence for opposing consequences of IL-23R on innate and adaptive lymphoid cells in murine colitis.
authors.affiliation: Department of Molecular Biology, Genentech, South San Francisco, California, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Cox
authors.forename: N M
authors.initials: NM
authors.lastname: Kljavin
authors.forename: N
authors.initials: N
authors.lastname: Ota
authors.forename: J
authors.initials: J
authors.lastname: Leonard
authors.forename: M
authors.initials: M
authors.lastname: Roose-Girma
authors.forename: L
authors.initials: L
authors.lastname: Diehl
authors.forename: W
authors.initials: W
authors.lastname: Ouyang
authors.forename: N
authors.initials: N
authors.lastname: Ghilardi
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000037:antagonists & inhibitors; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015431:Weight Loss / Q000187:drug effects / Q000235:genetics; D000097043:Interleukin-22
chemical_list: D004268:DNA-Binding Proteins; D016264:Dextran Sulfate; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C499308:Rag2 protein, mouse; C528688:interleukin-23 receptor, mouse