Resveratrol Regulates Microglia M1/M2 Polarization Via PGC-1α

Objective: Microglia are the primary cells that exert immune function in the central nervous system(CNS),and accumulating evidence suggests that microglia act as key players in the initiation of Parkinson’s disease(PD).It is now well recognized that microglia have functional plasticity and dual phenotypes,proinflammatory M1 and anti-inflammatory M2 phenotypes.Inhibiting the M1 phenotype while stimulating the M2 phenotype has been suggested as a potential therapeutic approach for the treatment of neuroinflammation-related diseases.Resveratrol has been demonstrated to exert anti-inflammatory effects by suppressing M1 microglia activation.However,the roles of resveratrol in regulating microglia polarization and the molecular mechanisms involved have not been fully clarified.We also measured the level of PPARγ coactivator-1α(PGC-1α)in PD patients and analysised its association with PD.Methods: We explored the role of resveratrol in microglia polarization by measuring M1 and M2 markers in vivo(LPS-induced neuroinflammatory injury mouse model)and in vitro(LPS-induced BV-2 cells)using Real-time PCR,western-blot and immunofluorescent assays.Then we tested whether PGC-1α was involved in the resveratrol-mediated microglia polarization in BV-2 cells by PGC-1α knockdown and overexpression methods.Lastly,we attempted to identify the underlying mechanism by which PGC-1α inhibits M1 polarization and promotes microglia M2 polarization using western-blot,CO-immunoprecipitation(CO-IP)and luciferase assays.We measured PGC-1α m RNA expression in peripheral blood mononuclear cells(PBMCs)through Real-time PCR from 42 PD patients and 42 healthy controls and explored the relationship between PGC-1α m RNA expression with disease severity.Results: 1.We demonstrated that resveratrol reduced inflammatory damage and promoted microglia polarization to the M2 phenotype in LPS-induced mice and BV-2 cells models.In addition,resveratrol ameliorated LPS-induced sickness behavior in mice.2.The promoting effects of resveratrol on M2 polarization were attenuated by knocking down PGC-1α.3.Overexpression of PGC-1α suppressed M1 microglia activation and promoted M2 polarization in conditions of LPS-induced neuroinflammatory injury in BV-2 cells.4.PGC-1α not only suppressed LPS-evoked M1 marker expression by inhibition of nuclear factor kappa B(NF-κB)activity but also increased M2 marker expression by coactivation of the signal transducers and activators of transcription 6(STAT6)and STAT3 pathways.5.Furthermore,PGC-1α was downregulated in peripheral blood mononuclear cells from PD patients and was correlated with disease severity.Conclusion: Our study demonstrated that PGC-1α was downregulated during neuroinflammation and that resveratrol could reduce inflammatory damage and promote microglia polarization to the M2 phenotype by increasing PGC-1α expression.PGC-1αnot only suppressed LPS-induced M1 activation by inhibition of NF-κB activity but also promoted microglia polarization to the M2 phenotype via activation of the STAT6 and STAT3 pathways.PGC-1α was downregulated in the peripheral blood mononuclear cells of PD patients and correlated with disease severity.