LRRK2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis

作者：Jessica Pei, Nathalia Luisa Oliveira, Sherilyn Junelle Recinto, Alexandra Kazanova, Celso Martins Queiroz‐Junior, Ziyi Li, Katalina Couto, Susan Westfall, Irah L. King, Camila Cristina Neves Romanato Ribeiro, Austen J. Milnerwood, Michel Desjardins, Ajitha Thanabalasuriar, Jo Anne Stratton, Samantha Gruenheid · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.11.26.625468 · 被引用次数：1 · 研究领域：Inflammatory Bowel Disease、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Immune Response and Inflammation

Abstract Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterised by motor and non-motor symptoms. Emerging evidence suggests a link between PD and gastrointestinal dysfunction. Constipation is frequently observed years prior to development of motor dysfunction in PD, and people with inflammatory bowel disease (IBD) are more likely to develop PD. Mutations in the leucine-rich repeat kinase 2 gene ( LRRK2 ) account for approximately 1% of all PD cases and are associated with increased risk for IBD. Among them, LRRK2 Gly2019Ser (G2019S), located within the kinase domain, is the most common PD-associated mutation and increases kinase activity. It is unknown how LRRK2 mutation affects susceptibility to intestinal inflammation or pathogenesis of PD. Using single cell RNA sequencing (scRNAseq), we demonstrate that LRRK2 G2019S mutation promotes a dysregulated gene profile, especially within neutrophil, monocyte and γδ T cell populations, following Citrobacter rodentium infection in mice. Transcriptionally, LRRK2 G2019S neutrophils have a greater pro- inflammatory type I and II IFN response compared to those of WT mice. This is accompanied by an increase in neutrophil numbers in the lamina propria in LRRK2 G2019S mice. We also uncover cell-intrinsic functional defects in LRRK2 G2019S neutrophils, including increased chemotaxis, degranulation and neutrophil extracellular traps (NETosis) formation. Increased neutrophil infiltration is associated with an upre...