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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.

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