IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis

Bofeng Li, Prajwal Gurung, R. K. Subbarao Malireddi, Peter Vogel, Thirumala-Devi Kanneganti and Terrence L. Geiger ()
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Bofeng Li: St Jude Children’s Research Hospital
Prajwal Gurung: St Jude Children’s Research Hospital
R. K. Subbarao Malireddi: St Jude Children’s Research Hospital
Peter Vogel: St Jude Children’s Research Hospital
Thirumala-Devi Kanneganti: St Jude Children’s Research Hospital
Terrence L. Geiger: St Jude Children’s Research Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7131

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