R1441C-Lrrk2突变以年龄和性别依赖的方式诱导小鼠髓系免疫细胞衰竭

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Rebecca L. Wallings, Karen McFarland, Hannah A. Staley, Noelle Neighbarger, Susen Schaake, Norbert Brüggemann, Simone Zittel, Tatiana Usnich, Christine Klein, Esther M. Sammler, Malú Gámez Tansey
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引用次数: 0

摘要

年龄是许多神经退行性疾病的最大风险因素,然而免疫系统老化作为神经退行性疾病的一个诱因却未得到充分研究。LRRK2 基因的遗传变异会影响家族性和散发性帕金森病(PD)的患病风险。富亮氨酸重复激酶 2 (LRRK2) 蛋白与外周免疫细胞信号传导有关,但老化的免疫系统对 LRRK2 功能的影响仍不清楚。我们分析了 R1441C-Lrrk2 基因敲入小鼠的腹腔巨噬细胞,观察到 R1441C-Lrrk2 突变对腹腔巨噬细胞功能的双相、年龄依赖性影响。我们报告了年轻(2 到 3 个月大)雌性 R1441C-Lrrk2 小鼠腹腔巨噬细胞抗原呈递、抗炎细胞因子产生、溶酶体活性和病原体摄取的增加。相反,年老(18 到 21 个月大)的雌性 R1441C-Lrrk2 小鼠的巨噬细胞在炎症损伤后表现出抗原呈递减少、溶酶体功能和病原体摄取减少,同时在病原体存在的情况下 DNA 断裂增加。在雄性 R1441C-Lrrk2 小鼠中没有观察到这种免疫细胞衰竭表型,这种表型是由 LRRK2 蛋白激酶活性增加驱动的。在人类外周髓系细胞中也观察到了这种表型,R1441C-或Y1699C-LRRK2突变的帕金森病患者的单核细胞衍生巨噬细胞对病原体的吸收减少,PDL1表达增加,这与免疫细胞衰竭一致。我们的研究结果表明,LRRK2突变会在年轻时带来免疫优势,但也会使携带者因年龄增长而导致免疫细胞衰竭,这对LRRK2抑制剂的治疗开发具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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