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

Authors

• Shun-Ming Ting
• Xiurong Zhao
• Guanghua Sun
• Mercedes Ricote
• Jaroslaw Aronowski

Language

English

Publication Date

9-10-2025

Journal

The Journal of Neuroscience

DOI

10.1523/JNEUROSCI.0248-25.2025

PMID

40803891

PMCID

PMC12424960

PubMedCentral® Posted Date

8-13-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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 proinflammatory 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 the 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 myeloid-RXRα–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 poststroke recovery in the aged brain.

Keywords

Animals, Microglia, Mice, Male, Female, Macrophages, Phagocytosis, Retinoid X Receptors, Mice, Inbred C57BL, Bexarotene, Stroke, Recovery of Function, Aging, Phenotype, aging, bexarotene, ischemic stroke, phagocytosis, poststroke recovery, retinoid X receptor

Published Open-Access

yes

Recommended Citation

Ting, Shun-Ming; Zhao, Xiurong; Sun, Guanghua; et al., "Retinoid-X-Receptor as a Mediator of Poststroke Recovery by Reversing Age-Associated Phenotypes of Microglia/Hematogenous Macrophages" (2025). Faculty, Staff and Student Publications. 3752.
https://digitalcommons.library.tmc.edu/uthmed_docs/3752