title: Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination.
abstract: Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling. When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator, macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B, particularly in combination with MCSF, increased the number of oligodendrocyte precursor cells and promoted remyelination within lesions; these pro-regenerative effects were mitigated in mice treated with clodronate liposomes to reduce circulating monocytes and tissue-infiltrated macrophages. Our results have identified candidates among currently used medications as potential therapies for the repair of myelin.
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and.
authors.forename: Axinia
authors.initials: A
authors.lastname: Döring
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and Grand River Hospital, Kitchener, Ontario N2G 1G3, Canada, and.
authors.forename: Scott
authors.initials: S
authors.lastname: Sloka
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Lau
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and.
authors.forename: Manoj
authors.identifier: http://orcid.org/0000-0001-9636-4930
authors.initials: M
authors.lastname: Mishra
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and.
authors.forename: Jan
authors.initials: J
authors.lastname: van Minnen
authors.affiliation: Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Kinniburgh
authors.affiliation: Centre Hospitalier Universitaire de Québec, Research Center and the Department of Molecular Medicine, Laval University, Québec, Québec G1V 4G2, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.affiliation: Hotchkiss Brain Institute and the Department of Clinical Neurosciences, and vyong@ucalgary.ca.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000502:physiology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D009186:Myelin Sheath / Q000187:drug effects* / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B; D016173:Macrophage Colony-Stimulating Factor
keywords: Amphotericin; innate immunity; macrophages; microglia; oligodendrocytes; remyelination