Abstract
The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
Highlights
Microglia were originally termed the ‘third element of nerve centers’ by Santiago Ramón yCajal at the beginning of the last century [1], but it was not until a few years later that his student, Pio Del Rio-Hortega, gave them their current name [2]
A number of toll-like receptors (TLR) are linked to neuroinflammatory processes in neurodegenerative diseases, for the purposes of this review we focused on toll-like receptor-4 (TLR4), as this is the best characterized in terms of signaling and pro-inflammatory response in microglia
TIR-domain containing adapter-inducing interferon-γ (TRIF) can interact with RIPK1 and RIPK3 [102], and activation of TLR3 and TLR4 in the presence of the pan-caspase inhibitor Z- Val-Ala-Asp(OMe)(VAD)-fluoro-methyl ketone in macrophages induces the formation of the TRIF/RIPK3 complex that leads to necroptosis [216]
Summary
Microglia were originally termed the ‘third element of nerve centers’ by Santiago Ramón y. Microglia progenitor cells originate in the yolk sac [7,8,9] from where they proliferate and migrate towards the CNS [10], maintaining homeostasis of the nervous tissue through permanent surveillance of the brain parenchyma [11] Throughout this process, microglia appear to undergo three stages of development defined in Matcovitch-Natan and colleagues [12], starting from early microglia until E14, followed by microglia from E14 to a few weeks after birth, and adult microglia from a few weeks after birth onward. We will begin by introducing the reader to pro-inflammatory signaling cascades in microglia, describing key players in the pro-inflammatory response during neurodegeneration as well as commenting on recent discoveries on the contribution of microglia to neuroinflammation This will be followed by a discussion of epigenetic regulation of inflammation, immunometabolism, and new technologies to overcome the current challenges of microglia research
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