Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.
Brain, 2015/12;138(Pt 12):3581-97.
Natrajan MS[1], de la Fuente AG[2], Crawford AH[2], Linehan E[3], Nuñez V[4], Johnson KR[5], Wu T[5], Fitzgerald DC[3], Ricote M[4], Bielekova B[5], Franklin RJ[6]
Affiliations
PMID: 26463675DOI: 10.1093/brain/awv289
Impact factor: 15.255
Abstract
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 RXRα (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.
Keywords: ageing; monocyte-derived macrophages; myelin debris; remyelination; retinoid X receptor
MeSH terms
Adult; Aging; Animals; Benzoates; Bexarotene; Biphenyl Compounds; Female; Humans; Macrophages; Male; Mice; Mice, Knockout; Middle Aged; Monocytes; Multiple Sclerosis; Myelin Sheath; Phagocytosis; Retinoid X Receptor alpha; Signal Transduction; Tetrahydronaphthalenes; Transcriptome; Young Adult
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