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.

中文翻译：

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R1441C-Lrrk2 突变以年龄和性别依赖性方式诱导小鼠骨髓免疫细胞耗竭


年龄是许多神经退行性疾病的最大风险因素，但导致神经退行性疾病的免疫系统衰老研究不足。LRRK2 基因的遗传变异会影响家族性和散发性帕金森病 （PD） 的风险。富含亮氨酸的重复激酶 2 （LRRK2） 蛋白与外周免疫细胞信号转导有关，但衰老免疫系统对 LRRK2 功能的影响仍不清楚。我们分析了来自 R1441C-Lrrk2 敲入小鼠的腹膜巨噬细胞，并观察到 R1441C-Lrrk2 突变对腹膜巨噬细胞功能的双相、年龄依赖性影响。我们报道了年轻 （2 至 3 个月大） 雌性 R1441C-Lrrk2 小鼠腹膜巨噬细胞中抗原呈递、抗炎细胞因子产生、溶酶体活性和病原体摄取的增加。相反，来自老年 （18 至 21 个月） 雌性 R1441C-Lrrk2 小鼠的巨噬细胞在炎症损伤后表现出抗原呈递降低、溶酶体功能和病原体摄取降低，在病原体存在下 DNA 片段化随之增加。这种免疫细胞耗竭表型在雄性 R1441C-Lrrk2 小鼠中未观察到，并且是由 LRRK2 蛋白激酶活性增加驱动的。在人外周骨髓细胞中也观察到这种表型，具有 R1441C 或 Y1699C-LRRK2 突变的 PD 患者的单核细胞衍生巨噬细胞表现出病原体摄取降低和 PDL1 表达增加，与免疫细胞耗竭一致。我们发现 LRRK2 突变在年轻时赋予免疫优势，但可能使携带者易患年龄获得性免疫细胞耗竭，这对 LRRK2 抑制剂的治疗开发具有意义。