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

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

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3581-3597
Number of pages17
JournalBrain
Volume138
Issue number12
Early online date13 Oct 2015
DOIs
Publication statusPublished - Dec 2015

Bibliographical note

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Keywords

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

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