TY - JOUR TI - LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis AU - Weindel, Chi G AU - Bell, Samantha L AU - Vail, Krystal J AU - West, Kelsi O AU - Patrick, Kristin L AU - Watson, Robert O A2 - Vance, Russell E A2 - Taniguchi, Tadatsugu A2 - Vance, Russell E VL - 9 PY - 2020 DA - 2020/02/14 SP - e51071 C1 - eLife 2020;9:e51071 DO - 10.7554/eLife.51071 UR - https://doi.org/10.7554/eLife.51071 AB - 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. KW - parkinson's disease KW - cGAS KW - DRP1 KW - purine biosynthesis KW - bacterial pathogenesis KW - metabolism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -