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J Exp Med. 2017 Oct 2;214(10):3051-3066. doi: 10.1084/jem.20170014. Epub 2017 Aug 18.

LRRK2 promotes the activation of NLRC4 inflammasome during Salmonella Typhimurium infection.

Author information

1
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Department of Immunology, Cleveland Clinic, Cleveland, OH.
3
Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4
Department of Urology, Cleveland Clinic, Cleveland, OH.
5
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
6
Department of Immunology, Cleveland Clinic, Cleveland, OH lix@ccf.org.
7
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH.
8
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China kangz@ccf.org.

Abstract

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.

PMID:
28821568
PMCID:
PMC5626397
DOI:
10.1084/jem.20170014
[Indexed for MEDLINE]
Free PMC Article

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