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Assessment of Vascular Regeneration in the CNS Using the Mouse Retina
Published on: June 23, 2014
Retinoid-X-Receptor as a Mediator of Poststroke Recovery by Reversing Age-Associated Phenotypes of
Shun-Ming Ting1, Xiurong Zhao1, Guanghua Sun1
1Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas 77030.
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.
Insights
Activating the retinoid X receptor (RXR) with bexarotene (BEX) improves stroke recovery in aged mice by restoring the phagocytic function of myeloid cells (MΦ). This treatment counteracts age-related MΦ dysfunction, enhancing brain repair after ischemic stroke.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Aging impairs myeloid cell (MΦ) phagocytosis and leads to overactivation, worsening secondary brain injury after stroke.
- Aged MΦ exhibit increased pro-inflammatory gene expression and decreased expression of phagocytosis-facilitating genes (e.g., Cd206, Cd36).
- Aging is a significant risk factor for stroke, associated with poorer neurological outcomes and mortality.
Purpose of the Study:
- To investigate if activating the retinoid X receptor (RXR) can reverse age-related MΦ dysfunction and improve stroke recovery.
- To determine the therapeutic potential of RXR activation in aged brains following ischemic stroke.
Main Methods:
- RNA sequencing was used to compare transcriptomes of MΦ from young and aged mice.
- In vivo phagocytosis models and a middle cerebral artery occlusion (MCAo) stroke model in male and female mice were employed.
- Treatment with the RXR agonist bexarotene (BEX) was administered to aged mice.
Main Results:
- BEX treatment reversed age-related gene expression changes in aged MΦ and enhanced their phagocytic ability.
- BEX administration improved sensorimotor and cognitive recovery in aged mice after MCAo.
- The therapeutic effects of BEX were dependent on myeloid-specific RXRα expression.
Conclusions:
- Activating RXRα partially restores age-related MΦ dysfunctions, improving post-stroke recovery in aged individuals.
- Targeting RXRα represents a potential therapeutic strategy to enhance brain repair after stroke in the elderly.
- RXRα deficiency in MΦ limits the beneficial effects of RXR activation on stroke recovery.
