Interferon gamma induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5

Abstract

The gene encoding leucine-rich repeat kinase 2 (LRRK2) is associated with familial and sporadic Parkinson's disease (PD), the second most common neurodegenerative disease. However, the role of LRRK2 in PD pathophysiology remains elusive. Recently, it has emerged that LRRK2 is highly expressed in the immune system including monocytes and macrophages and plays important roles in the immune system. LRRK2 has been reported to be induced by interferon-γ (IFN-γ) in macrophages, but the signaling pathway is not known. In this work, it was shown that LRRK2 is indeed induced upon IFN-γ stimulation. Importantly, IFN-γ-mediated induction of LRRK2 was suppressed by both pharmacological inhibition and RNA interference of the extracellular signal-regulated kinase 5 (ERK5). This was confirmed by LRRK2 immunocytochemistry, which also revealed that the morphological responses to IFN-γ were suppressed by ERK5 inhibitor treatment. Both human acute monocytic leukemia THP-1 cells and primary human peripheral blood monocytes stimulated the ERK5-LRRK2 pathway after differentiation into macrophages. Moreover, a transcriptome analysis of IFN-γ stimulated THP-1 cells co-treated with ERK5 inhibitors identified several targets putative downstream targets of LRRK2, which have to be further verified. In conclusion, this works establishes that LRRK2 is induced via a novel, ERK5-dependent IFN-γ signal transduction pathway. Moreover, it adds evidence that LRRK2 is involved in morphological alterations upon macrophage activation. The trancriptome analysis provides a list of candidate genes that may provide leads for future investigations to unravel LRRK2 immune cell function. In total, this is pointing to new functions of ERK5 and LRRK2 in human macrophages.