Although genetic polymorphisms in the LRRK2 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 Salmonella enteric serovar Typhimurium infection. LRRK2 deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages. Lrrk2^−/− mice exhibited impaired clearance of pathogens after acute S. 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.

尽管LRRK2基因的遗传多态性与多种疾病有关，但对LRRK2的生理功能仍然知之甚少。在这项研究中，我们报道了在抵抗沙门氏菌肠型血清鼠伤寒感染的宿主防御过程中，LRRK2在激活NLRC4炎性小体中起着至关重要的作用。LRRK2缺乏会降低巨噬细胞中对NLRC4炎性体激活剂的caspase-1激活和IL-1β分泌。Lrrk2 ^-/-小鼠在急性S后表现出对病原体的清除受损。鼠伤寒感染。从机理上讲，LRRK2在巨噬细胞中与NLRC4形成复合物，而LRRK2-NLRC4复合物的形成导致NLRC4在Ser533上发生磷酸化。重要的是，LRRK2的激酶活性是最佳NLRC4炎性体激活所必需的。总体而言，我们的研究通过促进NLRC4炎性体激活揭示了LRRK2在宿主防御中的重要作用。