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oai:repisalud.isciii.es:20.500.12105/151472024-09-27T08:02:26Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Natrajan, Muktha S author de la Fuente, Alerie G author Crawford, Abbe H author Linehan, Eimear author Nuñez, Vanessa author Johnson, Kory R author Wu, Tianxia author Fitzgerald, Denise C author Ricote, Mercedes author Bielekova, Bibiana author Franklin, Robin J M author Natrajan, Muktha S. author de la Fuente, Alerie G. author Crawford, Abbe H. author Johnson, Kory R. author Fitzgerald, Denise C. author Franklin, Robin J. M. author 2015-12 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. Brain . 2015 Dec;138(Pt 12):3581-97. 10.1093/brain/awv289 1460-2156 0006-8950 Brain : a journal of neurology 26463675 http://hdl.handle.net/20.500.12105/15147 Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.