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.

Keywords: ageing; macrophage; microglia; rejuvenation; white matter injury.

The nervous system’s capacity to repair itself declines with age. Rawji et al. discuss the effects of ageing on neurological diseases and propose that some of these effects may reflect differential senescence of macrophages and microglia. Therapeutic strategies to reverse macrophage/microglia senescence may promote regeneration in the ageing nervous system.

Figure 1

Phenotypic changes associated with macrophages and microglia during normal ageing. During ageing, senescent macrophages have decreased pro-inflammatory cytokine secretion, impaired phagocytosis and chemotaxis, and decreased proliferation. In contrast, senescent microglia display an elevation in pro-inflammatory cytokines and proliferative capacity, while showing a deficit in phagocytosis and motility.

Figure 2

Factors associated with ageing that negatively impact CNS regeneration. During normal ageing, changes in HSCs, macrophages, microglia, systemic peripheral and central factors, as well as shifts in the microenvironment composition may all contribute to the increased neurodegeneration and decreased repair observed in CNS injury in ageing subjects. CX3CR1 = chemokine (C-X3-C motif) receptor 1; CX3CL1 = chemokine (C-X3-C motif) ligand 1; CD200 = cluster of differentiation 200; CD200R = cluster of differentiation 200 receptor; TGF-β = transforming growth factor β; TNF-α = tumour necrosis factor α; MHCII = major histocompatibility complex II; CD68 = cluster of differentiation 68.

Figure 3

Therapeutic manipulation of ageing macrophages and microglia. As monocyte-derived macrophages age differently from CNS-intrinsic microglia, different therapeutic strategies are required to harness the benefits of these cells for CNS repair. Therapies that reverse HSC senescence, increase monocyte chemotaxis, enhance microglia and macrophage phagocytosis, generate a regulatory macrophage/microglia phenotype, and reduce toxic pro-inflammatory mediators are promising for repair of the injured and ageing CNS.