Microglia: Agents of the CNS Pro-Inflammatory Response

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.

Transcriptomic Analysis of Age-Associated Periventricular Lesions Reveals Dysregulation of the Immune Response

“…BST2 (CD317) is associated with inactivated microglia [24] and diminishes the expression of inflammatory genes [25]; therefore, BST2 was selected to identify the co-expressed genes associated with inactivated microglia. The phenotypic transformation from homeostatic microglia towards reactive microglia in dementia pathologies is associated with TREM2 [26], HLA-DRA [27], ENTPD1 (CD39) [28], CD80 (B7-1) [29], CD86 (B7-2) [10], CCR5 [30], CD274 [31], ITGAX (CD11c) [32], TIMD4 [33] and MRC1 [34]. Therefore, these candidates were used in the deconvolution analysis to identify co-expressed genes associated with active microglia in "pre-lesions" and PVL.…”

Early glycolytic reprogramming control microglial inflammatory activation

“…Overactivated microglial cells create a neuroin ammatory microenvironment by releasing various proin ammatory factors, thereby ultimately contributing to neurodegenerative progression [44]. Many studies have demonstrated that inhibition of microglial activation by anti-in ammatory compounds or modulation of the expression of some genes attenuated neuronal cell injuries under neurodegenerative conditions, suggesting that suppression of microglial activation may be considered a potential therapeutic approach to neurodegenerative diseases [45][46][47]. In the present study, we found that the glycolytic inhibitor 2-DG signi cantly inhibited neuronal cell death induced by conditioned media from activated microglial cells.…”

The Role of Natural Compounds and their Nanocarriers in the Treatment of CNS Inflammation

“…Microglial activation can be subdivided into M1 and M2 states. M1 microglia, which are pro-inflammatory cells, release inflammatory molecules such as ROS, RNS, and pro-inflammatory cytokines, and upregulate antigen proteins such as major histocompatibility complex class II [ 4 , 23 ]. In contrast, M2 microglia exhibit anti-inflammatory properties including release of anti-inflammatory cytokines such as interleukin 4 (IL-4), IL-10, and transforming growth factor-beta (TGF-β), leading to tissue repair [ 4 , 23 ].…”

“…Although various central nervous system (CNS) disorders, particularly CNS degenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), have become a bigger burden to individuals, families, and society, the molecular mechanisms and microenvironments of these disorders have not been fully understood. Neuroinflammation, which involves inflammatory cascades in nervous tissues, may be initiated in response to microglia/astrocyte activation, oxidative stress caused by reactive oxygen/nitrogen species (ROS/RNS), and mitochondrial excitotoxicity [ 1 , 2 , 3 , 4 , 5 ]. Sustained and prolonged neuroinflammation can result in persistent and chronic apoptotic neuronal cell death and programmed cell death (pyroptosis and necroptosis), thereby triggering various CNS degenerative disorders [ 2 , 6 , 7 ].…”