The R1441C-Lrrk2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the LRRK2 gene affects risk for both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from R1441C-Lrrk2 knock-in mice and observed a biphasic, age-dependent effect of the R1441C-Lrrk2 mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female R1441C-Lrrk2 mice. Conversely, macrophages from aged (18- to 21-month-old) female R1441C-Lrrk2 mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male R1441C-Lrrk2 mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the R1441C- or Y1699C-LRRK2 mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.