Ischemic stroke is a leading cause of death and long-term disability in elderly veterans. It is well established that post-stroke immune responses have a substantial impact on the progression of ischemic brain injury and brain recovery, but there are no clinical treatments that successfully harness the restorative power of the immune system while also tempering inflammation-induced secondary injuries. The reasons for this gap are multifactorial, but include a preclinical overemphasis on young adult animals, which simply do not display the same pathophysiological mechanisms underlying brain ischemia as the aged, including the dynamic inflammatory dialogue between glia and neurons. We propose to fill the critical gap in elderly veteran care by focusing on aged animals and repurposing an FDA-approved drug at low doses to correct hyperactive immune responses and tip the balance in favor of sustained tissue healing and long-term recovery of neurological functions. To commence this goal, we have conducted pilot studies on proteins that are highly enriched in microglia and brain-infiltrating macrophages (Mi/MΦ)—including the retinoid X receptor (RXR). RXR binds to peroxisome proliferator-activated receptor γ (PPARγ) to govern the transcription of genes critically involved in redox status, inflammation resolution, trophic factor production, and metabolism. Thus, RXR/PPARγ activation lies at the apex of a decision tree for arbitrating between polymorphic, often-opposing immune responses in Mi and MΦ. To engage this important biological target, we have chosen a selective RXR agonist, bexarotene, an FDA-approved antineoplastic agent lacking in pan-immunosuppressive effects and with excellent safety profiles. The scientific premise underlying the engagement of the RXR/PPARγ axis as a superior biological target for stroke is its ability to titrate immune balance toward anti-inflammatory/pro-repair phenotypes, while avoiding indiscriminate suppression of immune function in the vulnerable elderly. The premise of this proposal is also strengthened by our new preliminary discoveries: 1) Mi/MΦ-specific conditional knockout (mKO) of RXR or PPARγ worsens long-term outcomes after permanent distal middle cerebral artery occlusion (dMCAO) in mice. 2) RXR or PPARγ mKO mice exhibit impairments in post-stroke efferocytosis (Mi/MΦ phagocytosis of dying neurons) and resolution of neuroinflammation. 3) PPARγ mKO alters the Mi/MΦ transcriptome, with heightened proinflammatory responses and impaired phagocytosis according to RNA sequencing data. 4) Excitingly, intraperitoneal administration of low-dose bexarotene (10-20 times lower than in clinical trials) improves long-term outcomes after dMCAO in aged mice (20 months old). Accordingly, our research group is now in an excellent position to test the following core hypothesis: Activation of RXR improves long-term outcomes after ischemic stroke by promoting efferocytosis and inflammation-resolving, pro- repair microglial/macro...