title: Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.
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.
authors.affiliation: 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.
authors.forename: Muktha S
authors.initials: MS
authors.lastname: Natrajan
authors.affiliation: 1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK.
authors.forename: Alerie G
authors.initials: AG
authors.lastname: de la Fuente
authors.affiliation: 1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK.
authors.forename: Abbe H
authors.initials: AH
authors.lastname: Crawford
authors.affiliation: 3 Centre for Infection and Immunity, Queen's University Belfast, UK.
authors.forename: Eimear
authors.initials: E
authors.lastname: Linehan
authors.affiliation: 4 Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nuñez
authors.affiliation: 2 Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: 2 Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.affiliation: 3 Centre for Infection and Immunity, Queen's University Belfast, UK.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Fitzgerald
authors.affiliation: 4 Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ricote
authors.affiliation: 2 Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
authors.affiliation: 1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK rjf1000@cam.ac.uk Bibi.Bielekova@nih.gov.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D000077610:Bexarotene; D001713:Biphenyl Compounds / Q000494:pharmacology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects; D055815:Young Adult
chemical_list: D001565:Benzoates; D001713:Biphenyl Compounds; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; C438269:diazepinylbenzoic acid; D000077610:Bexarotene
keywords: ageing; monocyte-derived macrophages; myelin debris; remyelination; retinoid X receptor