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.
K E Y W O R D Sbrucellosis, caspase-1, innate lymphoid cell, NLRP3Recently, we reported that inflammasomes induce joint inflammation, but also contribute to control of infection during Brucella-induced arthritis. 15 Inflammasomes are multiprotein structures that use sensors, such as NLRP3 and AIM2, to detect intracellular, cytosolic threats. 16 Upon sensor activation, canonical inflammasomes recruit pro-caspase-1, and cleave it into its functional form, caspase-1.