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

      Research output: Research - peer-reviewArticle

      • Muktha S. Natrajan
      • Alerie G. de la Fuente
      • Abbe H. Crawford
      • Eimear Linehan
      • Vanessa Nunez
      • Kory R. Johnson
      • Tianxia Wu
      • Denise Fitzgerald
      • Mercedes Ricote
      • Bibiana Bielekova
      • Robin J.M. Franklin

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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 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.


      Original languageEnglish
      Pages (from-to)3581-3597
      Journal publication dateDec 2015
      Issue number12
      Early online date13 Oct 2015
      StatePublished - Dec 2015

      ID: 18097441