Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination

Natrajan, M S and De La Fuente, A G and Crawford, A H and Lineham, E and Nuñez, V and Johnson, K R and Wu, T and Fitzgerald, D C and Ricote, M and Bielekova, B and Franklin, R J (2015) Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. BRAIN, 138 (Pt12). pp. 3581-97.

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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.