Retinoid X Receptor as a Mediator of Post Stroke Recovery by Reversing Age-Associated Phenotypes of Microglia/Hematogenous Macrophages

After stroke, microglia/blood-derived macrophages, together MF, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the repair/recovery process. However, the phagocytic capability of MF declines with age. Furthermore, aged MF become overactivated in response to stroke, enhancing secondary brain injury. Now, demonstrate that by reversing the age-related dysfunctions in MF through activating the retinoid x receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA sequencing, we compared the transcriptomes between MF isolated from the brains of young and aged mice. We observed higher levels of pro-inflammatory genes and lower levels of phagocytosis-facilitating genes (Cd206, Cd36) expressed by aged MF. Meanwhile, the treatment with RXR agonist bexarotene (BEX) reversed the signature genes of microglia aging in the aged MF. With the in vivo phagocytosis model, we showed that BEX enhanced the phagocytic ability of aged MF. Using mouse MCAo stroke model, we established that BEX improved sensorimotor and cognitive recovery after MCAo in a myeloid-RXRa-specific and -dependent manner. In conclusion, we showed that activating RXRa partially restores age-related MF dysfunctions and that RXRa deficiency in MF limits the therapeutic effect of RXR in improving post-stroke recovery in the aged brain RNA-seq profiling of microglia/macrophages isolated from young (2-4 months old) and aged (18-20 months old) mice in response to RXR agonist bexarotene (BEX). The RNA-seq profiling of microglia/macrophages isolated from aged mice at Day3 after ischemic stroke (MCAo) treated with vehicle or BEX is also included.