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

Abstract

Leucine-rich repeat kinase 2 (Lrrk2) has received widespread attention as a risk gene associated with Parkinson's disease. As the immune response attributes of Parkinson's disease have been gradually revealed, the link between Lrrk2 and the immune system has emerged. Here, we demonstrated that Lrrk2 regulates macrophage function by promoting M1 polarization. Transcriptome and immunological analyses revealed that deletion of Lrrk2 in macrophages leads to blunted interferon (IFN)-γ and lipopolysaccharide (LPS)-stimulated M1 macrophage-associated gene expression and function. Mechanistically, Lrrk2 supports M1-associated immune effector signatures, including chemokines and inducible nitric oxide synthase (iNOS) expression, by enhancing signal transducer and activator of transcription 1 (STAT1) transcription factor signaling. The effect of Lrrk2 on macrophages is dependent on its kinase activity. These results revealed a previously uncharacterized role of Lrrk2 in M1 macrophage polarization by modulating cellular responses to cytokines and toll-like receptors (TLRs), such as IFN-γ and LPS.