Immunoregulation of Microglia M2 polarization is an unrecognized physiological function of α -Synuclein

Abstract BACKGROUNDMicroglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. It is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e. mostly desirable functions of microglia in a physiological state. What maintains microglia at this physiological state is essentially unknown, despite significant research on factors that provoke “reactive” or “inflammatory” phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson’s disease.METHODSIn this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ,IL-4 + IL-13, α-synuclein monomer and α-synuclein oligomer, examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP. RESULTS: We described a novel physiological function of α-synuclein, in which it modulates microglia towards an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways. CONCLUSIONS: These findings suggest a previously unrecognized function of α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.