2. Academic Validation
  3. Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination

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.
Muktha S Natrajan 1,  Alerie G de la Fuente 2,  Abbe H Crawford 2,  Eimear Linehan 3,  Vanessa Nuñez 4,  Kory R Johnson 5,  Tianxia Wu 5,  Denise C Fitzgerald 3,  Mercedes Ricote 4,  Bibiana Bielekova 5,  Robin J M Franklin 6
Affiliations

Affiliations

  • 1 1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK 2 Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 2 1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK.
  • 3 3 Centre for Infection and Immunity, Queen's University Belfast, UK.
  • 4 4 Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 5 2 Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 6 1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK [email protected] [email protected].
PMID: 26463675 DOI: 10.1093/brain/awv289
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.

Keywords

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

Figures