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

Natrajan, M S; De La Fuente, A G; Crawford, A H; Lineham, E; Nuñez, V; Johnson, K R; Wu, T; Fitzgerald, D C; Ricote, M; Bielekova, B; Franklin, R J

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.

Citation

Natrajan, M. S., De La Fuente, A. G., Crawford, A. H., Lineham, E., Nuñez, V., Johnson, K. R., Wu, T., Fitzgerald, D. C., Ricote, M., Bielekova, B., & Franklin, R. J. (2015). Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain, 138(Pt12), 3581-97. https://doi.org/10.1093/brain/awv289

• Journal Article Type: Article
• Acceptance Date: Aug 14, 2015
• Publication Date: Oct 13, 2015
• Deposit Date: Aug 23, 2018
• Journal: BRAIN
• Print ISSN: 0006-8950
• Electronic ISSN: 1460-2156
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 138
• Issue: Pt12
• Pages: 3581-97
• DOI: https://doi.org/10.1093/brain/awv289
• Public URL: https://rvc-repository.worktribe.com/output/1399458