LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

eLife

Chi G Weindel¹  Robert O Watson¹  Kelsi O West¹  Kristin L Patrick¹  Samantha L Bell¹  Krystal J Vail² 

[1] Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States;Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, United States;

关键词: parkinson's disease;    cGAS;    DRP1;    purine biosynthesis;    bacterial pathogenesis;    metabolism;    Human;    Mouse;    Other;   

DOI  :  10.7554/eLife.51071

来源: publisher

【 摘 要 】

The Parkinson’s disease (PD)-associated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferon (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

【 授权许可】

CC BY