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

Brain. 2015 Dec;138(Pt 12):3581-97. doi: 10.1093/brain/awv289. Epub 2015 Oct 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.

Keywords: ageing; monocyte-derived macrophages; myelin debris; remyelination; retinoid X receptor.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aging / metabolism*
  • Aging / pathology*
  • Animals
  • Benzoates / pharmacology
  • Bexarotene
  • Biphenyl Compounds / pharmacology
  • Female
  • Humans
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Multiple Sclerosis / metabolism
  • Myelin Sheath / metabolism*
  • Phagocytosis* / drug effects
  • Retinoid X Receptor alpha / agonists
  • Retinoid X Receptor alpha / antagonists & inhibitors
  • Retinoid X Receptor alpha / genetics
  • Retinoid X Receptor alpha / metabolism*
  • Signal Transduction / physiology
  • Tetrahydronaphthalenes / pharmacology
  • Transcriptome / drug effects
  • Young Adult


  • Benzoates
  • Biphenyl Compounds
  • Retinoid X Receptor alpha
  • Tetrahydronaphthalenes
  • diazepinylbenzoic acid
  • Bexarotene