Microglia-mediated neuroinflammation in neurodegenerative diseases

Subhramanyam, Charannya Sozheesvari; Wang, Cheng; Hu, Qidong; Dheen, S. Thameem

doi:10.1016/j.semcdb.2019.05.004

Cited by 635 publications

(447 citation statements)

References 163 publications

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“…Microglia, the resident immune cells of the central nervous system (CNS), maintain tissue homeostasis under physiological conditions [61]. However, after neuronal injury, microglia secrete pro-inflammatory cytokines that either have direct neurotoxic effects or, in combination with inflammatory chemokines, promote influx of circulating neutrophils in inflamed tissue [61].…”

Section: Modulation Of Microglial Activity: the Main Mechanism Responmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Harrell¹,

Jovičić

Djonov

et al. 2019

Cells

552

379

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There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.

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Section: Modulation Of Microglial Activity: the Main Mechanism Responmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Harrell¹,

Jovičić

Djonov

et al. 2019

Cells

552

379

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“…A growing body of evidence implicates that microglias in the active state can release various neurotoxic molecules [8,17], causing the loss of neurons in neurodegenerative diseases, including Alzheimer`s disease [18], ALS [20] and retinal degeneration [19]. Moreover, we and others have previously demonstrated that sera or IgG from patients with pediatric OMS and NB induces the cytolysis of cerebellar granular and cerebral cortical neurons [6,7].…”

Section: The No/sgc/pkg Pathway Takes Part In Neuronal Cytolysis Indumentioning

confidence: 91%

“…It has been established that activated microglias contribute to neuron death by secreting various neurotoxic molecules in multiple disorders [8,17] and serum IgG from patients with OMS and NB enhances neuronal death [6,7,36], we therefore explored whether neuronal cytolysis is enhanced by microglial activation in OMS. After getting rid of the remaining IgG, serum IgG-treated microglia conditioned media were collected and replaced the culture media of neurons.…”

Section: The Cytolysis Of Neurons Induced By Conditioned Media From Mmentioning

confidence: 99%

“…Although we found that proinflammatory cytokines, namely IL-1β, IL-6, TNF-α and MCP-1, were elevated in the media of microglias treated with IgG from patients with pediatric OMS and NB, and others reported that IL-6 in CSF of untreated OMS patients and IL-1 receptor antagonist in CSF of intravenous immune globulin-treated OMS patients are higher [37], the elevated cytolysis of cerebral cortical and cerebellar neurons induced by conditioned media from microglias preincubated with serum IgG was not influenced by these proinflammatory cytokines, indicating a specific effect of the NO pathway on neuronal cytolysis induced by microglial activation. Possible explanations are that cytokines secreted from microglias may take part in other functions rather than neuronal cytolysis, such as the recruitment of immune cells [8], and cytokines enhanced in patients with OMS may be produced by other cells, not microglias.…”

Section: The No/sgc/pkg Pathway Takes Part In Neuronal Cytolysis Indumentioning

confidence: 99%

“…Thus, it is reasonable to hypothesize that serum IgG from children with OMS and NB may impact the activation of microglia. {Heck, 1999 #57}Activated microglias release various neurotoxic molecules [8,17], causing the loss of neurons in neurodegenerative diseases [18][19][20]. In patients with pediatric OMS and NB, we and others have revealed that sera or IgG purified from sera causes cytolysis in cultured cerebellar and cerebral neurons [6,7].…”

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confidence: 99%

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Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

Ding

Yang

et al. 2020

Preprint

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BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare neurological disease. Some children with OMS also have neuroblastoma (NB). We and others have previously documented that serum IgG from children with OMS and NB induces neuronal cytolysis via several signaling pathways. However, mechanisms underlying OMS remain unclear. Here we investigated whether nitric oxide (NO) from activated microglias and its cascade contribute to neuronal cytolysis in pediatric OMS. MethodsThe activation of cultured cerebral cortical and cerebellar microglias incubated with sera or IgG isolated from sera of children with OMS and NB was measured by the expression of the activation marker, cytokines and NO. Neuronal cytolysis was determined after exposing to IgG-treated microglia conditioned media. Using inhibitors and activators, the effects of NO synthesis and its intracellular cascade, namely soluble guanylyl cyclase (sGC) and protein kinase G (PKG), on neuronal cytolysis were evaluated. ResultsIncubation with sera or IgG from children with OMS and NB increased the activation of cerebral cortical and cerebellar microglias, but not the activation of astrocytes or the cytolysis of glial cells.Moreover, the cytolysis of neurons was elevated by conditioned media from microglias incubated with IgG from children with OMS and NB, which was relieved by the inhibitors of NO signaling. By contrast, neuronal cytolysis was exacerbated by the activators of NO signaling but not proinflammatory cytokines. Neuronal cytolysis was suppressed by pretreatment with the microglial inhibitor minocycline, a clinically tested drug. Finally, increased microglial activation did not depend on the Fab fragment of serum IgG. ConclusionsSerum IgG from children with OMS and NB potentiates microglial activation, which induces neuronal cytolysis through the NO/sGC/PKG pathway, suggesting an applicability of microglial inhibitor as a therapeutic candidate. BackgroundOpsoclonus-myoclonus syndrome (OMS) is a rare but devastating neurological disease, characterized by opsoclonus, myoclonus and ataxia. Most patients suffer from persistent deficits in cognition, neurology and behavior. Some children with OMS also have neuroblastoma (NB), although varied percentages have been reported [1][2][3][4][5]. Previously, we have documented that the insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase cascade alleviates neuronal cytolysis induced by serum IgG from children with OMS and NB [6], others also reported that the phosphorylation of extracellular signal-regulated kinase contributes to neuronal cytolysis in pediatric OMS [7]. Yet, the cellular and molecular mechanisms associated with neuronal cytolysis underlying pediatric OMS remain unclear. Microglias are major immune effectors in the central nervous system (CNS) and have an important physiological function in inflammation [8]. Notably, patients with pediatric OMS exhibit increased expression of a microglial marker and proinflammatory cytokines in cerebrospinal fluid (CSF) and some children with OMS are post-inf...

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Association of Outdoor Ambient Fine Particulate Matter With Intracellular White Matter Microstructural Properties Among Children

et al. 2021

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Key Points Question Is annual residential exposure to particulate matter 2.5 μm or less in diameter (PM 2.5 ) associated with neuroimaging diffusion markers of white matter microstructure? Findings This cross-sectional study of 7602 children 9 to 10 years of age found evidence of an association between PM 2.5 exposure and hemispheric differences in white matter microstructure. In hemisphere-specific models, adjusted for confounding variables, statistically significant positive associations were observed between PM 2.5 and restricted isotropic diffusion, and statistically significant negative associations were observed between PM 2.5 and mean diffusivity. Meaning Findings from this study suggest that exposure to PM 2.5 may be associated with differences in white matter microarchitecture, supporting a need for further improvements in air quality to protect the developing brain.

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Microglia-mediated neuroinflammation in neurodegenerative diseases

Cited by 635 publications

References 163 publications

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

Association of Outdoor Ambient Fine Particulate Matter With Intracellular White Matter Microstructural Properties Among Children

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