Increasing studies show that inflammatory processes may be involved in depressive disorders.Nuclear factor erythroid-2 related factor 2 (Nrf2) modulates tissue microglial M1 phenotypic changes to the M2 phenotype,which is implicated in protection against inflammatory diseases.We have reported that the adipose-derived mesenchymal stem cells (ADSCs) display anti-inflammatory activity.In this study we explored whether the mechanism of anti-inflammatory activity of ADSCs was related to Nrf2.ADSCs were isolated from mouse fat pads and intravenously administered to chronic mild stress (CMS)-exposed C57BL/6 mice at the dose of 1 x 106 once a week for 3 weeks.We showed that ADSC administration significantly remedied CMS-induced depressive-like behaviors in sucrose preference test,tail suspension test,and forced swim test accompanied by suppressing microglial activation and the expression of inflammatory factors including MCP-1,TNF-α,IL-1β,and IL-6.Furthermore,ADSC administration promoted both the expression of BDNF and TrkB,and promoted Nrf2/HO-1 signaling but suppressed TLR4/NF-KB signaling in brain tissue.In order to elucidate the role of Nrf2/HO-1 signaling in ADSC-caused neuroprotection,Nrf2-modified ADSCs were cocultured with BV2 microglial cells,then exposed to lipopolysaccharide (LPS).Downregulation of Nrf2 in ADSCs decreased the protective effects of ADSCs against LPS-induced microglial activation and M1 polarization.Nrf2 overexpression in ADSCs markedly suppressed LPS-induced TLR4 and NF-KB expression in microglial cells.These results suggest a possible antidepressive mechanism correlated with microglial polarization for anti-inflammatory agents,which may provide a new microglia-targeted strategy for depression therapy.