Microglia: Housekeeper of the Central Nervous System

Abstract

Microglia, of myeloid origin, play fundamental roles in the control of immune responses and the maintenance of central nervous system homeostasis. These cells, just like peripheral macrophages, may be activated into M1 pro-inflammatory or M2 anti-inflammatory phenotypes by appropriate stimuli. Microglia do not respond in isolation, but form part of complex networks of cells influencing each other. This review addresses the complex interaction of microglia with each cell type in the brain: neurons, astrocytes, cerebrovascular endothelial cells, and oligodendrocytes. We also highlight the participation of microglia in the maintenance of homeostasis in the brain, and their roles in the development and progression of age-related neurodegenerative disorders.

Keywords: Astrocytes; Brain aging; CNS keeper; Microglia activation; Neurons; Oligodendrocytes.

Fig. 1

Origin of microglia during embryogenesis. Microglia originate from erythromyeloid progenitor cells from the yolk sac. They develop into embryonic microglia, regulated by transcription factors RUNX, PU.1, and IRF8. Embryonic microglia develop into mature microglia via factors such as IL-34 and CSF-1R

Fig. 2

Schematic diagram showing the complex interaction of microglia and cells that comprises the neurovascular unit in physiological and pathological conditions. A Neurons release immune-factors (calcium ion, Ca²⁺; fractalkine, CX3CL1; transforming growth factor-β, TGF-β; colony-stimulating factor-1, CSF1; Cluster of Differentiation 200, CD200; nucleotides (adenosine triphosphate, ATP), neurotransmitters (γ-aminobutyric acid, GABA; Serotonin), that bind to receptors on microglia, enhancing both physiological and pathological processes. B M1-activated microglia produce inflammatory mediators like cytokines (interleukin-1β, IL-1β; tumor necrosis factor-α, TNFα), prostaglandins (prostaglandin E2, PGE2), and neurotrophins (brain- derived neurotrophic factor, BDNF) whose receptors are found on neurons causing neurotoxicity. C Inflammatory factors (ROS, iNOS, TNF-α, IL-1β) from M1-activated microglia disrupt vascular endothelial cell capability to maintain BBB integrity altering the expression of important molecules, such as ZO-1, claudin-5, occludin, and permeability glycoprotein (P-gp). D Altered BBB giving way for the infiltration of tissue macrophage in the brain. E IL-4, IL-10, TGF-β activate microglia towards M2 phenotype. F LPS, substance-,P and IFN-γ activate microglia towards M1 phenotype. G Microglia have receptors for factors produced by astrocytes. On the other hand, receptors for the following mediators IL-1, CSF-1, and IL-2 produced by microglia are found on astrocytes. H Under steady state, resting microglia decrease apoptosis and facilitate differentiation of oligodendrocytes. I Oligodendrocytes also interact with microglia through production of various factors, production and uptake of exosomes, and the expression and activation of toll-like receptors, chemokine, and cytokine receptors. Excessive production of inflammatory and cytotoxic factors by M1 microglia damages oligodendrocytes. J Activated astrocytes inhibit M1-activated microglia, but activate distance microglia via calcium wave. K When microglia are activated, they produce inflammatory mediators which have the potentials for activating astrocytes

Fig. 3

The aged brain: physical and cellular changes. As the brain ages, there is a progressive and substantial loss of brain parenchyma, reduced oxygen and nutrients supply. This correlates with decreased cognitive function and susceptibility to neurodegeneration in cardiovascular and metabolic diseases. Brain injury is associated with microglia polarization to a M1 phenotype, which is pro-inflammatory and is characterized by increased DNA damage and ROS production, and altered regulation of mitochondria, lysosomes, and immune cells function, a process leading to a loss of brain homeostasis. This entire process is known as inflammaging