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 progressive, neurodegenerative disorder characterised by motor and non-motor symptoms. People with PD often present with gastrointestinal dysfunction, such as constipation, and studies have indicated that PD is more common in people with inflammatory bowel disease (IBD). Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are responsible for approximately 1% of all PD cases and increased risk for inflammatory bowel disease (IBD). Among them, the LRRK2 Gly2019Ser is the most common PD-associated mutation. It is unknown how LRRK2 mutation affects intestinal inflammation susceptibility or pathogenesis of PD. Here we demonstrate that LRRK2 G2019S mutation promotes increased neutrophils migration and differential gene regulation and cell function in these cells in Citrobacter rodentium-infected mice. We found a cell-intrinsic function for LRRK2 G2019S in vivo, in increasing neutrophil chemotaxis, degranulation and NETosis, and an upregulation of Th17 immune responses, which may together contribute to the observed increased colon pathology. Transcriptionally, these neutrophils have a greater pro-inflammatory type I and II IFN response compared to WT mice. Our results increase our understanding of the role of PD-associated genes in immune cells and their contribution to immune dysregulation, which could contribute to the development of pharmacological targets and biomarkers for an easier detection and intervention in PD. Overall design: Transcriptomic analysis of colonic lamina propria cells in LRRK2 G2019S mice compared to wild type following intestinal microbial infection