title: Immunosenescence of microglia and macrophages: impact on the ageing central nervous system.
abstract: Ageing of the central nervous system results in a loss of both grey and white matter, leading to cognitive decline. Additional injury to both the grey and white matter is documented in many neurological disorders with ageing, including Alzheimer's disease, traumatic brain and spinal cord injury, stroke, and multiple sclerosis. Accompanying neuronal and glial damage is an inflammatory response consisting of activated macrophages and microglia, innate immune cells demonstrated to be both beneficial and detrimental in neurological repair. This article will propose the following: (i) infiltrating macrophages age differently from central nervous system-intrinsic microglia; (ii) several mechanisms underlie the differential ageing process of these two distinct cell types; and (iii) therapeutic strategies that selectively target these diverse mechanisms may rejuvenate macrophages and microglia for repair in the ageing central nervous system. Most responses of macrophages are diminished with senescence, but activated microglia increase their expression of pro-inflammatory cytokines while diminishing chemotactic and phagocytic activities. The senescence of macrophages and microglia has a negative impact on several neurological diseases, and the mechanisms underlying their age-dependent phenotypic changes vary from extrinsic microenvironmental changes to intrinsic changes in genomic integrity. We discuss the negative effects of age on neurological diseases, examine the response of senescent macrophages and microglia in these conditions, and propose a theoretical framework of therapeutic strategies that target the different mechanisms contributing to the ageing phenotype in these two distinct cell types. Rejuvenation of ageing macrophage/microglia may preserve neurological integrity and promote regeneration in the ageing central nervous system.
authors.affiliation: 1 Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada vyong@ucalgary.ca.
authors.forename: Khalil S
authors.initials: KS
authors.lastname: Rawji
authors.affiliation: 1 Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: 1 Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Michaels
authors.affiliation: 2 Neuroscience Laboratory, CHU de Québec Research Centre, Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec City, Québec G1V 4G2, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.affiliation: 1 Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Stys
authors.affiliation: 1 Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
mesh_terms: D000375:Aging / Q000276:immunology / Q000473:pathology; D000818:Animals; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D006801:Humans; D000068884:Immunosenescence / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009422:Nervous System Diseases / Q000175:diagnosis / Q000276:immunology
keywords: ageing; macrophage; microglia; rejuvenation; white matter injury