Abstract 16: Retinoid X Receptors (RXR) Play Essential Roles In Improving Post-ischemic Stroke Recovery In Aged Brain By Restoring Age-associated Dysfunctions Of Microglia/macrophages

Abstract

After stroke, microglia and blood macrophages (MΦ) clear dead cells and cellular debris in the infarcted brain through phagocytosis. However, the phagocytic capability of MΦ declines with age. Age-related dysfunctions in MΦ also include reduced secretion of trophic factors, resulting in poor recovery after stroke. Retinoid-X-receptor (RXR) is a pleiotropic transcription factor. Our earlier studies suggest that RXR enhances MΦ phagocytic functions and improves post-stroke recovery in young mice. To assess MΦ dysfunctions with age, microglia were FACS-sorted from the brains of young adults (2-4 mo old) and aged (18-20 mo old) mice for gene expression profiling with qPCR. RXR agonist bexarotene (BEX; 5 mg/kg) or vehicle were IP injected daily for 3d prior to harvest (n=3/group). We found that compared to young adults, aged microglia have reduced expression of trophic factors ( Vegf ) and scavenger receptors ( Cd206 and Cd36 ) and that BEX treatment restored this deficit. Also, in agreement with gene expression profiles, using erythrocytes as targets for phagocytosis, we showed that BEX enhanced the phagocytic ability of MΦ in aged brain. This suggests that RXR activations restore the age-associated dysfunctions in MΦ.To further investigate the role of MΦ RXR activations in recovery after stroke, aged (18-20 months old) myeloid-specific RXRα knockout mice (Mac-RXRα-KO) and littermate control (RXRα-LoxP) of both sexes were subject to 60 min MCA occlusion. To activate RXR, BEX (5 mg/kg) or vehicle control was IP injected 24h after stroke onset and then daily for 7d (n=22/group). Sensorimotor functions were assessed using foot-fault and corner turn tests (d3, 7, 14, 28). The cognitive functions were evaluated via novel object recognition test (d30). We found that BEX significantly improved sensorimotor and cognitive functions in RXRα-LoxP mice. The beneficial effect of BEX was diminished in Mac-RXRα-KO mice, suggesting RXR signaling in MΦ plays essential role in recovery after stroke. Brain histology and serological cytokine profiles will also be discussed. In conclusion, our data show that activating RXR restores age-related dysfunctions in MΦ. More importantly, RXR in MΦ may be a potential target to improve post-stroke recovery in aged brain.