LRRK2 Mediates the Recruitment of Monocyte-Derived Macrophages to the Brain in Neurodegeneration Hisham Abdelmotilib1, Ravindra Bodhu1, Tyler Maltbie1, Aubrey Schonhoff1, Ashley Harms1, Andrew B. West1* 1Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35233 USA *Corresponding Author
Variation in the gene leucine-rich repeat kinase 2 encoding the LRRK2 protein has been associated with diseases associated with macrophage function and inflammation including mycobacteria infection, Crohn's disease, and Parkinson's disease. In our work with LRRK2 deficient mice and rats we have noticed fewer CD68+ cells recruited to the brain after intracranial injections of lipopolysaccharide, IFNγ, or rAAV2 virus expressing human α-synuclein. Others have likewise recorded dulled innate immune responses in the brain in LRRK2 knockout mice in HIV-TAT injection models and experimental uveitis models. However, under basal conditions, there appears no overt difference in immune cell composition between wild-type and knockout LRRK2 rodents. To gain further insight into the underlying deficiency in the stimulated LRRK2 knockout innate immune system, we localized LRRK2 expression in immune cells to monocyte-derived macrophages using fate mapping approaches. While LRRK2 expression is weak in circulating cells and macrophages in the vasculature, expression is robust in IFNγ-stimulated infiltrating macrophages that are distinct in origins from resident microglia that can comparably express CD68 and Iba1 when activated. Orally-available clinical-candidate LRRK2 small molecule inhibitors are recently available that can fully block LRRK2 kinase activity in rats. In rats treated with a LRRK2 small molecule inhibitor, we observed fewer monocyte-derived macrophages recruited to the brain in response to neurodegeneration. Ongoing studies in mature macrophages reveal that LRRK2 may play a critical role in endosome maturation and trafficking required for actin leading edge formation and chemokine receptor mobilization. While LRRK2 is expressed in numerous distinct types of cells throughout the body, we hypothesize that LRRK2 control over macrophage recruitment and responses in inflammation may explain part of the genetic associations observed in human diseases.
Funding- MJFF, NIH P20 NS09530, R01 NS064934, R21 NS097643, and the APDA
Credits: None available.
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