Microglia/macrophage (MΦ) are immune response cells with function in clearing cell debris and tissue repair after ischemic brain damage. Retinoid X receptor alpha (RXRα) is a pleiotropic transcription factor regulating cell differentiation, lipid/glucose metabolism and immune responses, including in MΦ. Studies from this lab suggest that the dimerization of RXRα with the peroxisome proliferator-activated receptor γ (PPARγ) to form a transcriptionally active structure plays critical roles in enhancing MΦ polarization toward the “healing” phenotype. All studies were performed applying scientific rigor. First, we showed that treatment of microglia in culture with selective agonist of the RXRα, bexarotene (BEX), promotes microglia’ polarization toward “beneficial” phenotype including enhancement of phagocytic functions toward engulfment of dead neurons. Next, we showed that BEX (5mg/kg, i.p.) given daily to rats after thromboembolic stroke reduced the infarct volume at d7. The neurological deficit was reduced by BEX at d7, but not at d3 after stroke. This suggest that the beneficial effects of BEX takes place during the sub-acute phase post-stroke. To further investigate the role of MΦ RXRα in ischemia, we generated macrophage-targeting RXRα knockout mice (MacRXRα-/-) by crossing Lyz-Cre mice with RXRαflox/flox mice. We subjected MacRXRα-/- and RXRαflox/flox (control) mice to a 60 min MCA/CCA reversible occlusion. 24h later mice received BEX (5mg/kg once a day for 7 days, i.p.) or vehicle. We conducted behavioral evaluations for 28 days. We showed, in agreement with the rat data, that control mice receiving BEX showed significant improvement in long-term neurological recovery and had reduced brain atrophy volume at d28 after stroke. We also showed that beneficial effect of BEX is significantly reduced in MacRXRα-/- mice, as compared to control mice. Limitation: Since MacRXRα-/- mice may also have RXRα deficiency in neutrophils, we are now conducting parallel studies to evaluate the role of RXRα deficiency in neutrophils. Our study suggests that RXRα in the MΦ may play important role in coordinating the cleanup and repair during post-stroke recovery phase. Also, we showed that BEX has the uniquely long 24h therapeutic window.