Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson's Disease (PD) and Crohn's Disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we developed a flow cytometry-based assay to assess LRRK2 activity in individual cells and created EGFP-LRRK2-knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we catalogued LRRK2 level and activity in splenic and intestinal tissues. Inflammation increased LRRK2 expression and activity in B-cells, immature neutrophils and immature monocytes, but decreased these in dendritic cells and eosinophils. In mature neutrophils, inflammation stimulated LRRK2 activity but reduced EGFP-LRRK2 level. A kinase-activating PD-associated R1441C-LRRK2 mutation exacerbated inflammation-induced activation of LRRK2 specifically in monocytes and macrophages without affecting LRRK2 levels. Finally, we identified IL-4 as a novel factor that upregulated LRRK2 expression and activity in B-cells in vitro, replicating the inflammatory effects observed in vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD. ### Competing Interest Statement MS and DRA received research funding for this project from Interline Therapeutics. AT is currently an employee of Amphista Therapeutics Ltd. MT is currently an employee of GlaxoSmithKline. The authors declare no other conflicts of interest. The funders did not play a role in the conceptualization, design, data collection, analysis, or preparation of the manuscript.