LRRK2 promotes the activation of NLRC4 inflammasome during <i>Salmonella</i> Typhimurium infection

Abstract

Although genetic polymorphisms in the <i>LRRK2</i> gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 in the activation of the NLRC4 inflammasome during host defense against <i>Salmonella enteric</i> serovar Typhimurium infection. <i>LRRK2</i> deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages. <i>Lrrk2^-/-</i> mice exhibited impaired clearance of pathogens after acute <i>S.</i> Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2-NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.