Investigating the Role of Leucine-Rich Repeat Kinase 2 (LRRK2) in the Innate Immune System

Abstract

Myeloid cells, such as monocytes and neutrophils, are generated in the bone marrow (BM) and are an important part of the innate immune system. Leucine-rich repeat kinase 2 (LRRK2) is a large, multi-domain protein that is expressed at high levels in the BM and myeloid cells. Agonistic mutations in the gene coding for LRRK2 promote better clearance of pathogens but have been identified as risk factors for inflammatory diseases, suggesting that LRRK2 may play a role in modulating the cell biology of innate immune cells. We aimed to decipher the cellular and molecular mechanisms impacted by enhanced LRRK2 kinase activity in a mouse typhoid model. Our results indicate that the agonistic p.G2019S mutation of Lrrk2 results in better clearance of Salmonella typhimurium (ST) in the BM, in comparison to wildtype mice. We also demonstrated that the p.G2019S mutation promotes maintenance of BM cell numbers following infection with ST. To further determine which BM cell types were most involved in the enhanced clearance of ST, we isolated bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs), monocytes, and neutrophils from adult mice. Following in vitro infection with ST, neutrophils, but not BMDMs, BMDCs, or monocytes harbouring the Lrrk2ᴳ²⁰¹⁹ˢ mutation, demonstrated a significant reduction in the bacterial burden of ST, relative to wildtype cells. Furthermore, our results indicate that neutrophils from Lrrk2ᴳ²⁰¹⁹ˢ mice demonstrate increased transcription of genes involved in the production of reactive oxygen species (ROS), along with higher levels of ROS following infection with ST, compared to wildtype neutrophils. Principally, the results of this project will provide new insights into the understanding of the impact of the agonistic Lrrk2ᴳ²⁰¹⁹ˢ mutation on the innate immune response to infection with ST.