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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE287142 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Astrogliosis is a hallmark of the response to brain ischemia, comprised of changes in gene expression and morphology. Hsp72 protects from cerebral ischemia, and although several mechanisms of protection have been investigated, effects on astrocyte activation are unknown. To identify potential mechanisms of protection, gene expression was assessed in mice subjected to middle cerebral artery (MCAO) or sham surgery, of either wildtype (WT) or Hsp72-overexpressing (Hsp72Tg) mice. After stroke, both genotypes exhibited genes related to cell death, stress response, and immune response. Furthermore, genes indicative of astrocyte activation, including cytoskeletal proteins and cytokines, were upregulated. To measure astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra after stroke using unbiased stereology. Consistent with other reports, we observed a marked and persistent increase in glial fibrillary acidic protein (GFAP ) as soon as 3 hours after MCAO. In contrast, vimentin immunoreactivity appeared 12-24 hours after stroke, peaked at 72 hours, and returned to baseline after 30 days. Surprisingly, no change in overall astrocyte number was observed based on glutamine synthetase (GS) immunoreactivity. To determine if Hsp72Tg mice exhibited altered astrocyte activation compared to WT controls, morphological evaluation by fractal analysis was used. Overexpression of Hsp72 reduced astrocyte cell area, arbor area, and to a lesser extent fractal dimension, 72 hours following stroke. In conclusion, in vivo overexpression of Hsp72 alters gene expression following stroke, including genes involved in astrocyte activation, and decreases astrocyte activation acutely following MCAO. Thus, modulation of astrogliosis may be a neuroprotective mechanism exerted by Hsp72 after ischemia. A total of 10 samples were analyzed, with 5 of each genotype, wildtype (WT) and Hsp72-overexpressing (Hsp72Tg) mice. Of the 5 in each group, 3 received middle cerebral artery occlusion (MCAO) and 2 received a sham surgery. The sham samples serve as the controls for the MCAO samples in each genotype. All samples were taken from the ischemic or control hemisphere 24 hours after surgery.

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

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