Journal
BRAIN
Volume 138, Issue -, Pages 3581-3597Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awv289
Keywords
remyelination; ageing; retinoid X receptor; myelin debris; monocyte-derived macrophages
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Funding
- UK Multiple Sclerosis Society
- Wellcome-Trust
- NINDS/NIH Intramural Research Program
- Health Research Board Scholars Program
- Gates-Cambridge Scholarship
- Spanish Ministry of Economy and Competitiveness [SAF2012-31483]
- BBSRC [BB/J01026X/1] Funding Source: UKRI
- MRC [MC_PC_12012] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J01026X/1] Funding Source: researchfish
- Medical Research Council [MC_PC_12012] Funding Source: researchfish
- Rosetrees Trust [M144] Funding Source: researchfish
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The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXR alpha (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.
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