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.
Elife. 2020 Feb 14;9:e51071. doi: 10.7554/eLife.51071.
The Parkinson's disease (PD)-associated gene leucine-rich repeat kinase 2 () has been studied extensively in the brain. However, several studies have established that mutations in 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 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 KO mice can control (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.
帕金森病（PD）相关基因富亮氨酸重复激酶 2（LRRK2）在大脑中已被广泛研究。然而，几项研究已经证实，LRRK2 中的突变使机体易感染分枝杆菌，表明 LRRK2 还控制着免疫。我们证明，巨噬细胞中 LRRK2 的缺失会导致 I 型干扰素（IFN）和干扰素刺激基因（ISGs）的基础水平升高，并导致对分枝杆菌病原体和细胞溶质核酸激动剂的干扰素反应迟钝。LRRK2 敲除（KO）巨噬细胞中先天免疫基因表达的改变是由多种线粒体应激驱动的，包括嘌呤代谢物水平低引起的氧化应激和 DRP1 依赖性线粒体碎片化。这些缺陷共同导致线粒体 DNA 泄漏到细胞质中，并持续激活 cGAS。虽然 LRRK2 KO 小鼠能够控制结核分枝杆菌（Mtb）的复制，但它们在肺部的炎症加剧和 ISG 表达降低。这些结果表明，LRRK2 依赖性线粒体缺陷在控制先天免疫结果方面存在以前未被认识到的后果。
