Lrrk2 promotes M1 macrophage polarization via regulating cytokine (IFN-γ) and TLR4 (LPS)-mediated responses

The research was led by Prof. Fuping Zhang from the Institute of Microbiology, Chinese Academy of Sciences, in collaboration with Prof. Jian Song from the Guangxi Zhuang Autonomous Region People's Hospital. The team's work sheds light on the pivotal role of Lrrk2, a major risk gene for Parkinson's disease, in modulating macrophage functions and immune responses.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and motor dysfunction. Recent research has increasingly linked the disease to immune system abnormalities, with genetic factors, particularly mutations in Lrrk2, emerging as critical contributors to disease onset and progression.

The team conducted a series of in vitro and in vivo experiments, including gene knockout mouse models, RNA sequencing, and immune signaling assays, to explore the role of Lrrk2 in macrophage-mediated immune responses. They found that LRRK2 expression is upregulated during bacterial infections and immune challenges, such as stimulation by Toll-like receptor ligands and IFN-γ, highlighting its regulation by immune-related stimuli.

Further analysis revealed that macrophages lacking Lrrk2 exhibited significantly reduced bacterial clearance, despite maintaining normal phagocytosis. Mechanistic studies showed that Lrrk2 promotes macrophage polarization toward the M1 phenotype by enhancing STAT1 phosphorylation in response to IFN-γ signaling. This function is dependent on the kinase activity of LRRK2, as confirmed by inhibitor experiments.

“Our findings provide compelling evidence that Lrrk2 plays a critical role in innate immune responses, particularly in driving M1 macrophage activation and effector function,” said Dr. Zhang. “This not only advances our understanding of the role of Lrrk2 in Parkinson's disease but also identifies potential therapeutic strategies targeting immune pathways.”

These findings not only enhance our understanding of the role of Lrrk2 in the innate immune system but also highlight its potential as a therapeutic target for immune-related disorders. By promoting M1 macrophage polarization and regulating downstream effector molecules, Lrrk2 significantly influences immune function. This study paves the way for future research on Lrrk2's role in immunity and its implications for innovative therapeutic strategies.

“These results offer new avenues for the treatment of immune-related diseases and deepen our understanding of Parkinson's disease beyond its neurological basis,” added Dr. Zhang. “Lrrk2 may emerge as a promising target for the development of therapies for both PD and autoimmune disorders.”

This work highlights the growing recognition of Lrrk2 as an immune-linked factor and lays the groundwork for future studies into Parkinson's disease as an immune-relate disease.