LRRK2 is required for macrophage homeostasis and the control of type I IFN

The use of genetic association studies has helped us appreciate that inflammation and immune dysfunction play an integral role in the pathology of multiple chronic disorders including cancer, type II diabetes, and neurodegenerative disease. We became interested in Leucine-rich repeat kinase 2 (LRRK2), a multifunctional kinase associated with Parkinson’s disease (PD), when it was revealed that LRRK2 polymorphisms are also associated with bacterial susceptibility to Mycobacterium leprae, a close relative of Mycobacterium tuberculosis, both of whose pathology relies heavily upon type I interferon (IFN), an innate immune response that activates effector cells. The regulation of type I IFN is critical to prevent a systemic inflammatory state and for the maintenance of healthy neurons. We therefore hypothesized that LRRK2 has a role in regulating innate immunity, contributing to both PD pathogenesis and bacterial infection. We found that in the absence of LRRK2 (Lrrk2−/−), macrophages failed to produce type I IFN in response to multiple cellular insults including, bacterial infection, mitochondrial damage, and DNA/RNA transfection. Interestingly the defect in type I IFN was a result of an imbalance at the level of the mitochondria, which altered macrophage homeostasis. These data suggest that LRRK2 is critical component of the innate immune system through its role maintaining mitochondrial health. The fact that LRRK2-deficient cells cannot induce type I IFN has major implications on both the maintenance of a proper cytokine milieu in the brain and management of the body’s immune response to infection.