Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15147
Título
Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.
Autor(es)
Natrajan, Muktha S | de la Fuente, Alerie G | Crawford, Abbe H | Linehan, Eimear | Nuñez, Vanessa | Johnson, Kory R | Wu, Tianxia | Fitzgerald, Denise C | Ricote, Mercedes CNIC | Bielekova, Bibiana | Franklin, Robin J M | Natrajan, Muktha S. | de la Fuente, Alerie G. | Crawford, Abbe H. | Johnson, Kory R. | Fitzgerald, Denise C. | Franklin, Robin J. M.
Fecha de publicación
2015-12
Cita
Brain . 2015 Dec;138(Pt 12):3581-97.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Phagocytosis | Adult | Aging | Animals | Benzoates | Bexarotene | Biphenyl Compounds | Female | Humans | Macrophages | Male | Mice | Mice, Knockout | Middle Aged | Monocytes | Multiple Sclerosis | Myelin Sheath | Retinoid X Receptor alpha | Signal Transduction | Tetrahydronaphthalenes | Transcriptome | Young Adult
Versión en línea
DOI
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- Nombre:
- Brain 2015 Retinoid X receptor ...
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- 2.471Mb
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