期刊论文详细信息
eLife
LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis
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
PDF
【 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   

【 预 览 】
附件列表
Files Size Format View
RO202004216811412ZK.pdf 2950KB PDF download
  文献评价指标  
  下载次数:14次 浏览次数:5次