Lrrk2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis

Parkinson’s Disease (PD) is a neurodegenerative disorder often preceded by gastrointestinal dysfunction. Mutations in leucine-rich repeat kinase 2 (LRRK2) are known risk factors for both PD and inflammatory bowel disease (IBD), suggesting a link between PD and the gastrointestinal tract. Using single-cell RNA-sequencing and spectral flow cytometry, we demonstrated that the Lrrk22 Gly2019Ser (G2019S) mutation is associated with an increased neutrophil presence in the colonic lamina propria during Citrobacter rodentium infection. This concurred with a Th17 skewing, upregulated Il17a, and greater colonic pathology during infection. In vitro experiments showed enhanced kinase-dependent neutrophil chemotaxis and neutrophil extracellular trap (NET) formation in Lrrk2 G2019S mice compared to wild-type counterparts. Our results add to the understanding of LRRK2-driven immune cell dysregulation and its contribution to PD, offering insights into potential biomarkers for early diagnosis and intervention in PD.帕金森病（Parkinson’s Disease, PD）是一类神经退行性疾病，其发病常先于胃肠功能障碍出现。富亮氨酸重复激酶2（leucine-rich repeat kinase 2, LRRK2）的突变是PD与炎症性肠病（inflammatory bowel disease, IBD）的已知危险因素，这提示PD与胃肠道之间存在密切关联。本研究借助单细胞RNA测序（single-cell RNA-sequencing）与光谱流式细胞术（spectral flow cytometry），证实Lrrk2 Gly2019Ser（G2019S）突变在啮齿类柠檬酸杆菌（Citrobacter rodentium）感染期间，与结肠固有层内中性粒细胞浸润增加显著相关。该表型同步伴随Th17细胞极化、Il17a表达上调，以及感染阶段更严重的结肠病理损伤。体外实验结果显示，与野生型小鼠相比，携带Lrrk2 G2019S突变的小鼠，其激酶依赖性中性粒细胞趋化能力与中性粒细胞胞外陷阱（neutrophil extracellular trap, NET）形成均显著增强。本研究结果进一步拓展了对LRRK2介导的免疫细胞失调机制及其在PD发病中作用的认知，为PD的早期诊断生物标志物开发与干预策略提供了全新的研究视角。