Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 91, P. 740 - 755

Published: Oct. 8, 2020

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes microglia are the principal cells that mediate CNS. Pattern recognition receptors (PRRs), expressed by astrocytes microglia, sense pathogen-derived endogenous ligands released damaged initiate immune response. Toll-like (TLRs) a well-characterized family of PRRs. The contribution microglial TLR signaling to CNS pathology has been extensively investigated. Even though assume wide variety key functions, information about role astroglial TLRs disease injuries is limited. Because display heterogeneity exhibit phenotypic plasticity depending on effectors present local milieu, they can exert both detrimental beneficial effects. modulators these paradoxical properties. goal current review highlight played diseases. We discuss host defense as well dissemination viral bacterial infections examine link between pathogenesis diseases evidence showing pivotal influence sterile inflammation injury. Finally, we define research questions areas warrant further investigations context astrocytes, TLRs, dysfunction.

Language: Английский

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Early glycolytic reprogramming controls microglial inflammatory activation

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: June 9, 2021

Microglial activation-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases. Inflammatory activation microglial cells is often accompanied by a metabolic switch from oxidative phosphorylation to aerobic glycolysis. However, roles and molecular mechanisms glycolysis are not yet fully understood.The anti-inflammatory effects its underlying glycolytic inhibition vitro were examined lipopolysaccharide (LPS) activated BV-2 or primary enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, immunoprecipitation, flow cytometry, nuclear factor kappa B (NF-κB) luciferase reporter assays. The neuroprotective inhibitor, 2-deoxoy-D-glucose (2-DG) vivo measured 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-or LPS-induced Parkinson's disease (PD) models immunofluorescence staining, behavior tests, blot analysis.We found that LPS rapidly increased cells, inhibitors (2-DG 3-bromopyruvic acid (3-BPA)), siRNA glucose transporter type 1 (Glut-1), hexokinase (HK) 2 abolished cell activation. Mechanistic studies demonstrated significantly inhibited mechanistic target rapamycin (mTOR), inhibitor factor-kappa kinase subunit beta (IKKβ), NF-kappa-B alpha (IκB-α), degradation IκBα, translocation p65 NF-κB, NF-κB transcriptional activity. In addition, 2-DG acetylation p65/RelA on lysine 310, which mediated NAD-dependent protein deacetylase sirtuin-1 (SIRT1) critical for A coculture study revealed reduced cytotoxicity microglia toward MES23.5 dopaminergic neuron with no direct protective effect. PD model, ameliorated subsequent tyrosine hydroxylase (TH)-positive loss. Furthermore, also death MPTP-induced model.Collectively, our results suggest actively involved Inhibition can ameliorate activation-related neuroinflammatory

Language: Английский

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Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(7), P. 3330 - 3330

Published: March 24, 2021

Alzheimer's disease (AD) is a debilitating neurological disorder, and currently, there no cure for it. Several pathologic alterations have been described in the brain of AD patients, but ultimate causative mechanisms are still elusive. The classic hallmarks AD, including amyloid plaques (Aβ) tau tangles (tau), most studied features AD. Unfortunately, all efforts targeting these pathologies failed to show desired efficacy patients so far. Neuroinflammation impaired autophagy two other main known It has reported that exist long before emergence any clinical manifestation Microglia inflammatory cells considered by many researchers as next hope finding viable therapeutic target Interestingly, it appears mitophagy also changed Inside cells, inflammation interact bidirectional manner. In current review, we briefly discussed an overview on then provided comprehensive discussion role pathways microglia their involvement pathogenesis.

Language: Английский

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Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Jan. 26, 2022

Mechanical damage is one of the predisposing factors inflammation, and it runs through entire inflammatory pathological process. Repeated or persistent damaging mechanical irritation leads to chronic diseases. The mechanism how forces induce inflammation not fully understood. Piezo1 a newly discovered mechanically sensitive ion channel. channel opens in response stimuli, transducing signals into an cascade cell leading tissue inflammation. A large amount evidence shows that plays vital role occurrence progression This mini-review briefly presents new responds different stresses trigger various tissues. discovery provides insights for treatment diseases related stress. Inhibiting transduction can inhibit improve outcome at early stage. pharmacology has shown bright prospects. development tissue-specific drugs clinical use may be target treating

Language: Английский

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Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson's disease model

Neuropharmacology, Journal Year: 2022, Volume and Issue: 207, P. 108963 - 108963

Published: Jan. 19, 2022

Language: Английский

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Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 1869 - 1869

Published: Jan. 18, 2023

Aging is the most prominent risk factor for late-onset Alzheimer’s disease. associates with a chronic inflammatory state both in periphery and central nervous system, evidence thereof mechanisms leading to neuroinflammation being discussed. Nonetheless, significantly enhanced by accumulation of amyloid beta accelerates progression disease through various pathways discussed present review. Decades clinical trials targeting 2 abnormal proteins disease, tau, led many failures. As such, via different strategies could prove valuable therapeutic strategy, although much research still needed identify appropriate time window. Active focusing on identifying early biomarkers help translating these novel from bench bedside.

Language: Английский

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Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(7)

Published: July 20, 2022

Abstract The advent of high-throughput single-cell transcriptomic analysis microglia has revealed different phenotypes that are inherently associated with disease conditions. A common feature some these activated is the upregulation galectin-3. Representative examples include disease-associated (DAM) and white-associated (WAM), whose role(s) in neuroprotection/neurotoxicity a matter high interest community. In this review, we summarise main findings demonstrate ability galectin-3 to interact key pattern recognition receptors, including, among others, TLR4 TREM2 importance regulation activation. Finally, discuss increasing evidence supporting involvement lectin neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s Huntington’s amyotrophic lateral sclerosis, multiple traumatic brain injury, stroke.

Language: Английский

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Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 15(1), P. 15 - 34

Published: Oct. 16, 2024

Neuroprotection is a proactive approach to safeguarding the nervous system, including brain, spinal cord, and peripheral nerves, by preventing or limiting damage nerve cells other components. It primarily defends central system against injury from acute progressive neurodegenerative disorders. Oxidative stress, an imbalance between body's natural defense mechanisms generation of reactive oxygen species, crucial in developing neurological Due its high metabolic rate consumption, brain particularly vulnerable oxidative stress. Excessive ROS damages essential biomolecules, leading cellular malfunction neurodegeneration. Several disorders, Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple ischemic stroke, are associated with Understanding impact stress these conditions for new treatment methods. Researchers exploring using antioxidants molecules mitigate aiming prevent slow down progression diseases. By understanding intricate interplay scientists hope pave way innovative therapeutic preventive approaches, ultimately improving individuals' living standards.

Language: Английский

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A New Strategy for the Regulation of Neuroinflammation: Exosomes Derived from Mesenchymal Stem Cells

Cellular and Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 44(1)

Published: Feb. 19, 2024

Abstract Neuroinflammation is an important pathogenesis of neurological diseases and causes a series physiopathological changes, such as abnormal activation glial cells, neuronal degeneration death, disruption the blood‒brain barrier. Therefore, modulating inflammation may be therapeutic tool for treating diseases. Mesenchymal stem cells (MSCs), pluripotent have great potential due to their regenerative ability, immunity, ability regulate inflammation. However, recent studies shown that MSC-derived exosomes (MSC-Exos) play major role in this process key neuroprotection by regulating neuroglia. This review summarizes progress made neuroinflammation focusing on mechanisms which MSC-Exos are involved regulation through signaling pathways TLR, NF-κB, MAPK, STAT, NLRP3 provide some references subsequent research therapy. Graphical Exosomes derived from MSCs exhibit neuroprotective effects mitigating triggered cells.

Language: Английский

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Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: July 21, 2021

Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial signaling can exacerbate issues chronic This review discusses for the interaction damage inflammation, with a focus on glaucomatous neurodegeneration, proposes that positive feedback resulting from this drives pathology. exacerbates multiple ways. Damaged DNA is damage-associated molecular pattern, which activates NLRP3 inflammasome; priming activation of inflammasome, liberation IL-1β IL-18 via gasdermin D pore, major pathway enhance responses. The rise reactive oxygen species induced by also pathways, while blockage Complex enzymes increase signaling. Impaired mitophagy contributes inflammation as inability turnover mitochondria timely manner increases levels ROS mtDNA, latter likely stimulate cGAS-STING interferon associated ER membrane contacts mitochondria-associated adaptor molecule MAVS activate inflammasome In addition dysfunctional increasing corollary occurs, reducing function ATP production; downward spiral accelerates degeneration. Evidence several preclinical models including DBA/2J mouse, microbead injection transient elevation IOP, patient data, implicates neurodegeneration. pressure-dependent hypoxia metabolic vulnerability release. Links occur retinal ganglion cells, microglia cells astrocytes. summary, increased enhances implications other complex neurodegenerations like Alzheimer’s Parkinson’s disease.

Language: Английский

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