Debris clearance by microglia: an essential link between degeneration and regeneration

Abstract

Microglia are cells of myeloid origin that populate the CNS during early development and form the brain's innate immune cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic avenues.

Fig. 1

Microglial phagocytic receptors. Phagocytosis is associated with inflammation during uptake of microbes, while phagocytosis of apoptotic cells is executed without inflammation. Recognition of microbes induces a microglial phagocytic response, which is associated with release of pro-inflammatory mediators such as TNF and NO. Particularly, TLRs recognize microbial patterns leading to pro-inflammatory activity release in microglial cells. Furthermore, Fc-receptor (FcR) engagement antibodies binding induces pro-inflammatory activity dependent of the Fc-receptor subtyp and antibody isotype. Recognition and phagocytosis of apoptotic cells induces an anti-inflammatory cytokine profile in microglia. Phosphatidylserine receptors (PRs) recognizing phosphatidylserine residues in apoptotic membranes stimulated microglial production and release of TGF-β and IL-10. Triggering receptor expressed on myeloid cells-2 (TREM2) induces anti-inflammatory activity of microglia. Purine receptors (PRs) such as P2Y6 are recognizing UDP. Phagocytic receptors: PRs = purine receptors; PSRs = phosphatidylserine receptors; CRs = complement receptors; TLRs = toll like receptors; FcR = Fc-receptors; SRs = scavenger receptors; TREM2 = triggering receptor expressed on myeloid cells-2. Soluble mediators: TNF = tumour necrosis factor-α; IL-1 =interleukin-1β; NO = nitric oxide; TGF-β = transforming growth factor-β; IL-10 = interleukin-10.

Fig. 2

Detrimental effects of myelin debris and extracellular aggregates (A) Inhibitory activity of myelin debris in multiple sclerosis. Immune mediated demyelination and oligodendrocyte injury liberates myelin. Myelin debris inhibits axonal re-growth and regeneration. Furthermore, myelin debris inhibits oligodendrocyte precursor cell differentiation. (B) Neurotoxic activity of Aβ plaques in Alzheimer disease. Extracellular Aβ directly damages synapses and stimulates microglial to release neurotoxic mediators such as TNF-α and nitric oxide (NO). Microglial cytotoxic mediators induces synaptic and axonal injury.

Fig. 3

Beneficial microglia function. Microglial beneficial function is mediated via several effector mechanisms. Firstly, microglia and invading macrophages clear myelin debris or extracellular aggregates. Secondly, microglia initiate the repair process by stimulating neighbouring astrocytes to produce trophic support factors and by recruiting stem and precursor cells. Thirdly, microglial cells produce a variety of neurotrophins, growth factors and anti-inflammatory cytokines stimulating sprouting of axons and myelin repair. Soluble mediators: BDNF = brain derived neurotrophic factor; NT3 = neurotrophin-3; IGF-1 = insulin-like growth factor-1; IL-10 = interleukin-10; IL-1 = interleukin-1; TNF = tumour necrosis factor-α; TGF-β = transforming growth factor-β.