Microglia: Agents of the CNS Pro-Inflammatory Response

Rodríguez‐Gómez, José A.; Kavanagh, Edel; Engskog-Vlachos, Pinelopi; Engskog, Mikael K.R.; Herrera, Antonio J.; Espinosa-Oliva, Ana M.; Joseph, Bertrand; Hajji, Nabil; Venero, José L.; Burguillos, Miguel Ángel

doi:10.3390/cells9071717

Cited by 228 publications

(162 citation statements)

References 413 publications

(529 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Fadul

Heath

Cooper‐Knock

et al. 2020

IJMS

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White matter lesions (WML) are a common feature of the ageing brain associated with cognitive impairment. The gene expression profiles of periventricular lesions (PVL, n = 7) and radiologically-normal-appearing (control) periventricular white matter cases (n = 11) obtained from the Cognitive Function and Ageing Study (CFAS) neuropathology cohort were interrogated using microarray analysis and NanoString to identify novel mechanisms potentially underlying their formation. Histological characterisation of control white matter cases identified a subgroup (n = 4) which contained high levels of MHC-II immunoreactive microglia, and were classified as “pre-lesional.” Microarray analysis identified 2256 significantly differentially-expressed genes (p ≤ 0.05, FC ≥ 1.2) in PVL compared to non-lesional control white matter (1378 upregulated and 878 downregulated); 2649 significantly differentially-expressed genes in “pre-lesional” cases compared to PVL (1390 upregulated and 1259 downregulated); and 2398 significantly differentially-expressed genes in “pre-lesional” versus non-lesional control cases (1527 upregulated and 871 downregulated). Whilst histological evaluation of a single marker (MHC-II) implicates immune-activated microglia in lesion pathology, transcriptomic analysis indicates significant downregulation of a number of activated microglial markers and suggests established PVL are part of a continuous spectrum of white matter injury. The gene expression profile of “pre-lesional” periventricular white matter suggests upregulation of several signalling pathways may be a neuroprotective response to prevent the pathogenesis of PVL.

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Section: Discussionmentioning

confidence: 99%

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

Fadul

Heath

Cooper‐Knock

et al. 2020

IJMS

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Early glycolytic reprogramming control microglial inflammatory activation

Cheng¹,

Zhang²,

Ke³

et al. 2020

Preprint

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Background Microglial activation-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases. Inflammatory activation of microglial cells is often accompanied by a metabolic switch from oxidative phosphorylation to aerobic glycolysis. However, the roles and molecular mechanisms of glycolysis in microglial activation and neuroinflammation are not yet fully understood.Methods The anti-inflammatory effects and its underlying mechanisms of glycolytic inhibition in vitro were examined in LPS activated BV-2 microglia or primary microglia cells by ELISA, RT-PCR, Western blot, immunoprecipitation, FACS and NF-κB luciferase reporter assays. The anti-inflammatory and neuroprotective effects of glycolytic inhibitor, 2-DG in vivo were measured in the MPTP-or LPS-induced PD models by immunofluorescence staining, behavior tests and Western blot analysis. Results We found that LPS rapidly increased glycolysis in microglial cells, and glycolysis inhibitors (2-DG and 3-BPA), siRNA Glut-1 and siRNA HK Ⅱ abolished LPS-induced microglial cell activation. Mechanistic studies demonstrated that glycolysis inhibitors significantly inhibited LPS-induced phosphorylation of mTOR, IKKβ and IκB, degradation of IκB, nuclear translocation of p65 and NF-κB transcriptional activity. In addition, 2-DG significantly inhibited LPS-induced acetylation of p65/RelA on lysine 310, which is mediated by NAD+-dependent SIRT1 and is critical for NF-kB activation. A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect. An in vivo study demonstrated that 2-DG significantly ameliorated neuroinflammation and subsequent DA neuronal cell injuries in an LPS-induced Parkinson’s disease (PD) model. Furthermore, 2-DG also reduced TH-positive cell loss and microglial activation in the MPTP-induced PD model. Conclusions Collectively, our results suggest that glycolysis is actively involved in microglial activation and, hence, that inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.

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“…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 ].…”

Section: Neuroinflammation and Cns Degenerative Diseasesmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Neuroinflammation, which is involved in various inflammatory cascades in nervous tissues, can result in persistent and chronic apoptotic neuronal cell death and programmed cell death, triggering various degenerative disorders of the central nervous system (CNS). The neuroprotective effects of natural compounds against neuroinflammation are mainly mediated by their antioxidant, anti-inflammatory, and antiapoptotic properties that specifically promote or inhibit various molecular signal transduction pathways. However, natural compounds have several limitations, such as their pharmacokinetic properties and stability, which hinder their clinical development and use as medicines. This review discusses the molecular mechanisms of neuroinflammation and degenerative diseases of CNS. In addition, it emphasizes potential natural compounds and their promising nanocarriers for overcoming their limitations in the treatment of neuroinflammation. Moreover, recent promising CNS inflammation-targeted nanocarrier systems implementing lesion site-specific active targeting strategies for CNS inflammation are also discussed.

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Microglia: Agents of the CNS Pro-Inflammatory Response

Cited by 228 publications

References 413 publications

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

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

Early glycolytic reprogramming control microglial inflammatory activation

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

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