LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to <i>Mycobacterium tuberculosis</i>.

Abstract

The Parkinson's disease (PD)-associated gene leucine-rich repeat kinase 2 (<i>LRRK2</i>) has been studied extensively in the brain. However, several studies have established that mutations in <i>LRRK2</i> 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 <i>Lrrk2</i> 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 <i>Lrrk2</i> KO mice can control <i>Mycobacterium tuberculosis</i> (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.