Microglia at the Crossroads of Pathogen-Induced Neuroinflammation

Abstract

Microglia are the resident tissue macrophages of the central nervous system (CNS). Recent findings point out that in the steady state the major role of microglia, is to instruct and regulate the correct function of the neuronal networks and different components of the neurovascular unit in the adult CNS, while providing immune surveillance. Paradoxically, during CNS infection immune activation of microglia generates an inflammatory milieu that contributes to the clearance of the pathogen but can, in the process, harm nearby cells of CNS. Most of the knowledge about the harmful effects of activated microglia on CNS has arisen from studies on neurodegenerative diseases. In this review we will focus on the beneficial role and detrimental functions of microglial cells on the neighboring cells of the CNS upon infection.

Keywords: CNS infection; immunopathology; microglia; neuroinflammation.

Figure 1.

Physiological functions of microglia. (A) Phagocytosis of apoptotic neurons. Apoptotic neurons release “find-me” signals which attract microglia and expose in their surface “eat-me” signals stimulating microglial phagocytosis. (B) Phagocytosis of viable neural progenitor cells. Microglia phagocytoses viable neural progenitor cells in a direct manner, without inducing apoptosis. (C) Trophic support of proliferation, survival and differentiation of neural and other glial progenitor cells. Microglia secrete trophic factors that promote neurogenesis, astrogenesis and oligodendrogenesis. (D) Refinement of synaptic formation and pruning. Microglia regulate the extension of synaptic networks through phagocytosis during CNS development, as well as in the adult CNS.

Figure 2.

Microglial immune receptors. Microglia recognize, through different pattern recognition receptors (PRRs), microorganisms that are capable of invading the CNS parenchyma. (A) Toll-like receptors (TLR) sense PAMPs expressed in microorganisms. TLR activation leads to the enrollment of the adaptor MyD88 and the consequent activation of MAPK that triggers the translocation to the nucleus of the transcription factor NF-κB, promoting the expression of many inflammatory cytokines and the precursor forms of IL-1β and IL-18. (B) Nod-like receptors (NLR) are cytosolic receptors that oligomerize, and together with adaptor proteins form the inflammasome. This multi-subunit complex activates caspase 1 (CASP-1) enzyme, which produce the proteolytic cleavage of pro-IL-1β and pro-IL-18 to their mature forms that are then released to the extracellular milieu. (C) GMP-AMP synthase (cGAS) is a cytosolic receptor that recognizes double-stranded DNA. The activation of cGAS produces the second messenger cGAMP, which binds to STING in the ER and promotes downstream IFN-β expression via IRF-3.

Figure 3.

Microglial phagocytic receptors. Microglia express several membrane phagocytic receptors that recognize different target molecules (“eat-me” signals) on apoptotic or live damaged neurons. The recognition can be direct or mediate by the interaction with bridge molecules. LacNac, N-acetyl-lactosamine; PE, phosphatidylethanolamine.

Figure 4.

Microglial primary phagocytosis or phagoptosis. Pathogen-activated microglia increase their phagocytic activity and secrete several pro-inflammatory mediators. These mediators induce the expression of “eat-me” signals on live neurons. The exposure of these signals in viable damaged neurons triggers neuronal death by microglial primary phagocytosis.