IFN-?-dependent nitric oxide suppresses Brucella-induced arthritis by inhibition of inflammasome activation.

ABSTRACT: Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a globally important zoonotic disease for which arthritis is the most common focal complication in humans. Wild-type mice infected systemically with Brucella typically do not exhibit arthritis, but mice lacking IFN-? develop arthritis regardless of the route of Brucella infection. Here, we investigated mechanisms by which IFN-? suppresses Brucella-induced arthritis. Several cell types, including innate lymphoid cells, contributed to IFN-? production and suppression of joint swelling. IFN-? deficiency resulted in elevated joint IL-1? levels, and severe joint inflammation that was entirely inflammasome dependent, and in particular, reliant on the NLRP3 inflammasome. IFN-? was vital for induction of the nitric oxide producing enzyme, iNOS, in infected joints, and nitric oxide directly inhibited IL-1? production and inflammasome activation in Brucella-infected macrophages in vitro. During in vivo infection, iNOS deficiency resulted in an increase in IL-1? and inflammation in Brucella-infected joints. Collectively, this data indicate that IFN-? prevents arthritis both by limiting Brucella infection, and by inhibiting excessive inflammasome activation through the induction of nitric oxide.

SUBMITTER: Lacey CA 

PROVIDER: S-EPMC6597291 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature