title: IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis.
abstract: Polymorphisms attenuating IL-10 signalling confer genetic risk for inflammatory bowel disease. Yet, how IL-10 prevents mucosal autoinflammation is incompletely understood. We demonstrate using lineage-specific deletions of IL-10Rα that IL-10 acts primarily through macrophages to limit colitis. Colitis depends on IL-6 to support pathologic Th17 cell generation in wild-type mice. However, specific ablation of macrophage IL-10Rα provokes excessive IL-1β production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity. IL-10 not only inhibits pro-IL-1β production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1β to IL-1β. Therefore, lineage-specific effects of IL-10 skew the cytokine dependency of Th17 cell development required for colitis pathogenesis. Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennesse 38105, USA.
authors.forename: Bofeng
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennessee 38105, USA.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennessee 38105, USA.
authors.forename: R K Subbarao
authors.initials: RK
authors.lastname: Malireddi
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennesse 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennessee 38105, USA.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Pl., Memphis, Tennesse 38105, USA.
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Geiger
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D019070:Cell Lineage; D003092:Colitis / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D058847:Inflammasomes; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012306:Risk; D015398:Signal Transduction; D058504:Th17 Cells / Q000378:metabolism*; D019076:Transgenes
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; C556062:IL10 protein, mouse; C507764:Il1rn protein, mouse; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C064658:RAG-1 protein; D016753:Interleukin-10; D020170:Caspase 1