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.
- 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].
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.