The Role Of PPAR-? Pathway In Phenotypic Changes Of Microglia

Activated microglia is involved in a variety of central nervous system(CNS)diseases,including depression,Alzheimer's disease(AD)and autism spectrum disorder(ASD).The activated phenotypes of microglia include M1(classical activation)and M2(alternative activation),which play distinct biological functions in the brain.M1-activated microglia mainly express pro-inflammatory cytokines that aggravate neuroinflammation,cause tissue damage,and play a neurotoxic role.While M2-activated microglia express more anti-inflammatory cytokines and neurotrophic factors,which could inhibit neuroinflammation response,promote tissue repair,and play a neuroprotective role.Therefore,it is of great significance to research the transformation mechanism of activation phenotypes in microglia.In this study,we investigated the homeostasis regulation of microglia exposed to Interferon gamma(IFN-?)by detecting changes in microglial activation phenotypes,and further explored the potential molecular mechanism in this process.The properties of microglia,including morphology,cytokines,and their effects on proliferation and differentiation of neural stem/progenitor cells(NSPCs)were analyzed to determine which activated phenotype microglia were in.Our results suggested that microglia treated with IFN-? for a period of time would not persistently present as neurotoxic M1-activated phenotype.Our data showed that the activations of microglia underwent a transition from M1 to M2 after 48 h of IFN-? treatment,while expression of anti-inflammatory cytokines and neurotrophic factors increased gradually.Correspondingly,the microglia showed functional transformation from neurotoxic to neuroprotective,shown as promoted proliferation and differentiation of NSPCs and increased maturation of newborn neurons.Our further studies showed that peroxisome proliferators-activated receptor-gamma(PPAR-?)was involved in the process of phenotypic transformation of activated microglia.After 48 h of IFN-? treatment,the expression level of PPAR-? protein showed a significant increased trend.Subsequently,the antagonist GW9662 and agonist Pioglitazone of PPAR-? were used respectively on the IFN-?-treated microglia.Our results showed that GW9662 blocked the transformation of microglia into M2 type,while pre-treated of Pioglitazone would accelerate the process of transformation.Next,we further verified the effects of activated PPAR-? signal pathway on the phenotypic transformation of activated microglia induced by IFN-? in vivo.Intracerebroventricular injection of IFN-? leaded to pro-inflammatory cytokines' promotion and anti-inflammatory cytokines' reduction in cortex and hippocampus,as well as a series of behavior damage,including the abated social ability in social interaction test and the increased immobility time in tail suspension test.While pre-treated Pioglitazone would effectively reverse these phenomena induced by IFN-?.These results indicated that IFN-? activated microglia exhibited a time-dependent phenotypic transition,in which the PPAR-? signal pathway played a key role.