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Human genetic variants associated with mitochondrial dysfunction have been linked to chronic inflammatory diseases as well as susceptibility to infection. However, the mechanistic impact that these variants have on the immune system is poorly understood. We have discovered that macrophages harboring the common Parkinson’s disease associated variant, Lrrk2G2019S are more prone to cell death in response to both Mycobacterium tuberculosis (Mtb) infection and AIM2 inflammasome activation. Unexpectedly, the enhanced cell death in Lrrk2G2019S macrophages is driven by increased susceptibility to gasdermin D (GSDMD)-mediated mitochondrial pore formation, which releases accumulated mitochondrial ROS and pushes Lrrk2G2019S cells to undergo RIPK3-mediated necroptosis. Consistent with elevated necroptotic cell death, infection of Lrrk2G2019S mice with Mtb elicits dramatic hyperinflammation and exacerbated pathogenesis via enhanced neutrophil infiltration. Remarkably, expression of hLRRK2G2019S in Drosophila melanogaster recapitulates a similar phenotype, suggesting that Lrrk2G2019S plays an evolutionarily conserved role in regulating innate immunity. Our findings demonstrate that altered mitochondrial function can reprogram canonical innate immune and cell death pathways to elicit distinct immune outcomes, providing mechanistic insights into why mutations in LRRK2 are associated with susceptibility to chronic inflammatory and infectious diseases. Supported by grants from the Parkinson's Foundation (PF-FBS-1932), NIH (R01 AI125512), Michael J. Fox Foundation (grant 12185), and the Texas A&M Clinical Science and Translational Research (CSTR) Pilot Grant Program.

Leucine-rich repeat kinase 2 (LRRK2), a multifunctional kinase linked to Parkinson’s disease (PD), has been repeatedly implicated in mycobacterial infection, although it’s function outside the nervous system is poorly understood. To create a replicative niche within the harsh environment of a macrophage, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), needs to manipulate two major innate immune pathways, the type I IFN response and regulated cell death (RCD). Previously, we found that loss of LRRK2 (Lrrk2−/−) in macrophages results in type I IFN defects during Mtb infection in vitro and in vivo. We mechanistically linked this type I IFN reprogramming to LRRK2-dependent mitochondrial dysfunction and leakage of mtDNA into the macrophage cytosol. To further investigate the role of LRRK2 in Mtb pathogenesis, we shifted focus to the G2019S variant of LRRK2, which is the greatest genetic risk factor for PD. While the type I IFN response is normal in Lrrk2G2019S macrophages, their mitochondrial network is fragmented and depolarized. These macrophages also are more prone to a pyroptotic form of regulated cell death (RCD) that is dependent on mtDNA. Importantly, during Mtb infection in vivo, Lrrk2G2019S mice experience hyperinflammation and elevated signatures of pyroptotic cell death. Collectively, these data suggest that Lrrk2G2019S impairs mitochondrial health and enhances inflammatory cell death (pyroptosis) with severe in vivo consequences during Mtb infection. The potent enhanced inflammatory response present in the periphery of G2019S mice in vivo might begin to suggest a model where increased inflammation in the periphery could trigger or exacerbate neurodegeneration in carriers of this allele.

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.