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

After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ 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 MΦ isolated from the brains of young and aged male mice. We observed higher levels of pro-inflammatory genes and lower levels of phagocytosis-facilitating genes ( Cd206 and Cd36 ) expressed by aged MΦ. Meanwhile, the treatment with RXR agonist bexarotene (BEX) reversed the signature genes of microglia aging in the aged MΦ. With the in vivo phagocytosis model, we showed that BEX enhanced the phagocytic ability of aged MΦ. Using MCAo stroke model and male and female mice, we established that BEX improved sensorimotor and cognitive recovery after MCAo in a myeloid-RXRα-specific and -dependent manner. In conclusion, we showed that activating RXRα partially restores age-related MΦ dysfunctions and that RXRα deficiency in MΦ limits the therapeutic effect of RXR in improving post-stroke recovery in the aged brain. Significance Statement Aging is the most robust unmodifiable risk factor for ischemic stroke. The majority of stroke patients are individuals older than 65 years (Virani et al., 2020). Aging is also a predictor for worse outcomes (increased neurological deficit and mortality) after stroke. Despite this, only a limited number of studies attempted to elucidate the differences in post-stroke recovery between young and elderly subjects. One likely reason for worse repair/recovery in aged subjects after stroke is the decline in phagocytic and reparative properties of aged MΦ (Hefendehl et al., 2014; Koellhoffer et al., 2017). Aged MΦ may fail to clear cell debris and pro-inflammatory molecules from the ischemic brain, thereby worsening secondary injury and recovery after stroke (Shen et al., 2019).