Despite many connections between mutations in leucine-rich repeat kinase 2 (
LRRK2) and susceptibility to mycobacterial infection, we know little about its function outside of the brain, where it is studied in the context of Parkinson’s Disease (PD). Here, we report that LRRK2 controls peripheral macrophages and brain-resident glial cells’ ability to respond to and express inflammatory molecules. LRRK2KO macrophages express elevated basal levels of type I interferons, resulting from defective purine metabolism, mitochondrial damage, and engagement of mitochondrial DNA with the cGAS DNA sensing pathway. While LRRK2KO mice can control Mycobacterium tuberculosis(Mtb) infection, they exhibit exacerbated lung inflammation and altered activation of glial cells in PD-relevant regions of the brain. These results directly implicate LRRK2 in peripheral immunity and support the “multiple-hit hypothesis” of neurodegenerative disease, whereby infection coupled with genetic defects in LRRK2create an immune milieu that alters activation of glial cells and may trigger PD.