Inflammasomes promote the initiation of Brucella induced arthritis in an IL-18 dependent manner and mediate Brucella clearance independently of IFN-γ

Abstract

Abstract Brucellosis, caused by the intracellular bacterial pathogen Brucella, is a zoonotic disease for which infection of the joints is the most common focal complication in humans. The purpose of this study was to identify if Brucella activation of inflammasomes and in turn caspase1/11 activation is responsible for inducing arthritis. Here we report caspase-1/11−/− (casp1/11−/−) mice had reduced swelling, inflammation and inflammatory cytokine levels early in infection relative to wild-type “WT” mice. Later in infection, joint inflammation was similar between WT and casp1/11−/− mice, but bacterial loads and swelling were greater in casp1/11−/− joints. While IL-1Rdeficiency reduced joint swelling, this effect occurred later and was not of the same magnitude as casp1/11 deficiency, indicating an IL-1 independent role of casp1/11. Casp1/11 induced inflammation was partially dependent on IL-18, and IFN-γ levels were reduced in both casp1/11−/− and IL-18-deficient mice relative to WT mice early in infection. However, while IFN-γ and casp1/11 both played a role in controlling joint Brucella burdens, an additive effect of these deficiencies was observed indicating that the protective effects of IFN-γ and casp1/11 on bacterial clearance are not interdependent. Enhanced arthritis and musculoskeletal inflammation was observed in IFN-γ-deficient, relative to WT mice. However, neutralization of IFN-γ in casp1/11−/− mice did not result in enhanced inflammation. Collectively these data demonstrate casp1/11 induces early inflammation in an IL-18 dependent manner. Moreover, there is an IFN-γ independent role of casp1/11 in joint Brucella clearance, and casp1/11 is responsible for enhanced inflammation observed in IFN-γ-deficient mice.