Nlrp3-dependent IL-1? inhibits CD103+ dendritic cell differentiation in the gut.

ABSTRACT: Inflammatory bowel disease (IBD) is associated with enhanced levels of the IL-1 family cytokines IL-1? 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? induces Th17 polarization and increases GM?CSF production by T cells. Reduced IL-1? 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? 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?.

SUBMITTER: Mak'Anyengo R 

PROVIDER: S-EPMC5922280 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature