title: IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism.
abstract: Polymorphisms of interleukin (IL)-23R and signaling components are associated with several autoimmune diseases, including inflammatory bowel diseases (IBD). Similar to T helper type 17 (Th17) lineage, type 3 innate lymphoid cells (ILCs) express retinoic acid-related orphan receptor γt (Rorγt) and IL-23R and hence, produce Th17-type cytokines. Recent reports implicated type 3 ILCs in IBD; however, how IL-23R signaling in these cells contributes to pathogenesis is unknown. IL-22, produced in copious amounts by type 3 ILCs, was reported to have both beneficial and pathogenic effects in adaptive, yet only a protective role in innate colitis models. Herein, by employing chronic CD45RB(high) CD4(+) T-cell transfer and anti-CD40 antibody-induced acute innate colitis models in Rag1(-/-) mice, we demonstrated opposite roles for IL-23R in colitogenesis: in the former a protective, and in the latter a pathogenic role. Furthermore, we show that IL-23R signaling promotes innate colitis via IL-22 as neutralization of IL-22 protected mice from colitis and adding back of IL-22 to IL-23R-deficient animals restored the disease. Collectively, our results reveal that similar to its controversial role during chronic or adaptive colitis, IL-22 may also have opposite roles in innate colitis pathogenesis in a context and insult-dependent manner.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: A
authors.initials: A
authors.lastname: Eken
authors.affiliation: Seattle Children's Research Institute, Center for Immunity and Immunotherapies, Seattle, Washington, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Comparative Medicine School of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: 1] Department of Immunology, University of Washington, Seattle, Washington, USA [2] Seattle Children's Research Institute, Center for Immunity and Immunotherapies, Seattle, Washington, USA.
authors.forename: M
authors.initials: M
authors.lastname: Oukka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D007378:Interleukins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C528688:interleukin-23 receptor, mouse