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-10R? 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-10R? provokes excessive IL-1? production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity. IL-10 not only inhibits pro-IL-1? production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1? to IL-1?. 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.

SUBMITTER: Li B 

PROVIDER: S-EPMC4302761 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature