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Introduction: The immune response to cerebral ischemia is a major contributor to stroke pathobiology in which microglia play a crucial role. Microglia are present in the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory microglia. The Nur77 is a member of orphan nuclear receptor family, has been implicated in the regulation of macrophage M1/M2 polarization. However, the function of Nur77 in microglia and stroke pathology has not been studied yet. We investigated the role of Nur77 in modulating microglial M1/M2 polarization and improve brain injury.Methods: Wild type and Nur77-/- mice were subjected to right middle cerebral artery occlusion (MCAO). Behavior test, infarction volume, inflammation factors, and microglial phenotypes were determined at 1d, 3d, 7d after MCAO. In vitro, wild type and Nur77-/- microglia were simulated with conditional medium of oxygen glucose deprivation neuron. M1/M2 markers were measured at different time points. To explore mechanisms, proteomics analysis was conducted. Then we induced a lentivirus into the microglial cells for abrogation of Nur77 downstream protein in Nur77-/- microglia.Results: Nur77 expression in ipsilateral peri-infarction is markedly decreased. Nur77 deficiency enlarged infarction size, exacerbated sensorimotor and cognitive function, increased the expression of pro-inflammatory mediators (COX-2, TNFα), and decreased anti-inflammatory mediators (IL-4, IL-10) at 3d and 7d after MCAO. Nur77-/- mice present more CD16+Iba-1+ and CD86+Iba-1+ M1 microglia and less CD206+Iba-1+ M2 microglia than wild type mice. In vitro conditional medium treated Nur77-/- primary microglia express more pro-inflammation mediators and less anti-inflammation factors. LPS-treated Nur77-/- and wild type microglia was used for mass spectrometry and we found that Nur77 down-regulate the expression of dedicator of cytokinesis 2 (DOCK2), which promote release of proinflammation mediators in microglia. After knockdown of DOCK2 in Nur77-/- microglia, up-regulated pro-inflammation mediators in Nur77-/- microglia have been reversed.Conclusions: Nur77 protects against ischemic brain injury by promoting M2 polarization, which probably be mediated by DOCK2-dependent pathway.