Myeloid Cell–Specific Retinoid X Receptor Signaling Facilitates White Matter Repair and Stroke Recovery in Aged Mice

BACKGROUND: As stroke is the leading cause of long-term disability in the elderly, effective pharmacological therapies for neurorestoration remain an unmet clinical need. RXR (retinoid X receptor) signaling regulates inflammation and tissue repair, but the downstream repair processes linking RXR activation to stroke recovery in the aged central nervous system remain incompletely defined. We used aged mice to test the hypotheses that (1) pharmacological RXR stimulation with the brain-penetrant pan-RXR agonist bexarotene boosts poststroke recovery and (2) myeloid cell-specific RXR signaling facilitates white matter repair and underlies the therapeutic effects of bexarotene. METHODS: Permanent focal cerebral ischemia was induced in 18- to 22-month-old C57BL/6 male and female mice by distal middle cerebral artery occlusion. Pharmacological RXR activation and genetic ablation were achieved by poststroke bexarotene administration and generation of myeloid cell-specific RXR conditional knockout mice, respectively. Functional (sensorimotor and cognitive performance) and structural measures of central nervous system recovery were assessed up to 35 days after stroke. RESULTS: Poststroke treatment with bexarotene (5-10 mg/kg) improved sensorimotor performance in the rotarod, foot fault, and adhesive removal tests and alleviated cognitive deficits in the Morris water maze and passive avoidance tests. Bexarotene improved white matter integrity at 35 days after distal middle cerebral artery occlusion, without impacting white matter at 3 days or preventing gray matter atrophy at chronic injury stages. Bexarotene also suppressed immune cell infiltration and proinflammatory cytokine production, enhanced inflammation-resolving efferocytosis, promoted long-term oligodendrogenesis and angiogenesis, and fostered a prorepair central nervous system microenvironment. Accordingly, stroke outcomes were markedly worsened in aged RXR conditional knockout mice compared with age-matched wild-type mice, and the functional and white matter benefits of bexarotene were blocked in RXR conditional knockout mice. CONCLUSIONS: Myeloid RXR signaling promotes long-term stroke recovery in aged mice of both sexes and engages anti-inflammatory and prorepair mechanisms. Bexarotene warrants further evaluation as a potential neurorestorative therapy for stroke.