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Mak'Anyengo, Rachel; Duewell, Peter; Reichl, Cornelia; Hoerth, Christine; Lehr, Hans-Anton; Fischer, Sandra; Clavel, Thomas; Denk, Gerald; Hohenester, Simon; Kobold, Sebastian; Endres, Stefan; Schnurr, Max; Bauer, Christian (2018): Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut. In: Jci Insight, Vol. 3, No. 5, e96322
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Inflammatory bowel disease (IBD) is associated with enhanced levels of the IL-1 family cytokines IL-1 beta and IL-18, which are activated by the Nlrp3 inflammasome. Here, we investigated the role of inflammasome-driven cytokine release on T cell polarization and DC differentiation in steady state and T cell transfer colitis. In vitro and in vivo data showed that IL-1 beta induces Th17 polarization and increases GM-CSF production by T cells. Reduced IL-1 beta levels in Nlrp3(-/-) mice correlated with enhanced FLT3L levels and increased frequency of tolerogenic CD103(+) DC. In the T cell transfer colitis model, Nlrp3 deficiency resulted in lower IL-1 beta levels, reduced Th17 immunity, and less severe colitis. Unaltered IL-18 levels in both mouse strains pointed toward Nlrp3-independent processing. Importantly, cohousing revealed that the gut microbiome had no impact on the observed Nlrp3(-/-) phenotype. This study demonstrates that NLRP3 acts as a molecular switch of intestinal homeostasis by shifting local immune cells toward an inflammatory phenotype via IL-1 beta.