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1.
J Neuroinflammation ; 20(1): 20, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36721258

RESUMO

Chronic microglia activation post-stroke is associated with worse neurological and cognitive outcomes. However, measurement of microglia activation in vivo is currently limited. Plasma derived extracellular vesicles (EVs) are cell-specific indicators that may allow for non-invasive measurement of microglia phenotype. The aim of this study was to identify activation-state specific microglia EVs (MEVs) in vitro followed by validation in an experimental stroke model. Following pro-inflammatory activation, MEVs contain the microglia protein TMEM119 alongside increased expression of the Toll-like receptor 4 co-receptor CD14. Immunoprecipitation followed by fluorescent nanoparticle tracking analysis (ONI Nanoimager) was used to confirm the isolation of TMEM119+/CD14+ EVs from rat plasma. Electron microscopy confirmed that TMEM119 and CD14 localize to the MEV membrane. To model ischemia, plasma was collected from 3-month wildtype Fischer344 rats prior to, 7 and 28 days after endothelin-1 or saline injection into the dorsal right striatum. Fluorescently labelled MEVs were directly measured in the plasma using nanoflow cytometry (Apogee A60 Microplus). We report a significant increase in circulating TMEM119+/CD14+ EVs 28-days post-stroke in comparison to baseline levels and saline-injected rats, which correlated weakly with stroke volume. TMEM119+/MHC-II+ EVs were also increased post-stroke in comparison to baseline and saline-injected animals. This study is the first to describe an EV biomarker of activated microglia detected directly in plasma following stroke and represents a future tool for the measurement of microglia activity in vivo.


Assuntos
Vesículas Extracelulares , Microglia , Acidente Vascular Cerebral , Animais , Ratos , Biomarcadores , Corpo Estriado , Fenótipo
2.
Biol Pharm Bull ; 46(2): 359-363, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36724966

RESUMO

Amyloid ß (Aß) plays a key role in the pathology of Alzheimer's disease (AD) and is toxic owing to its ability to aggregate into oligomers and fibrils. Aß has high aggregative ability and potent toxicity due to the "toxic turn" at positions 22 and 23. Furthermore, APP knock-in mice producing E22P-Aß with the toxic turn exhibited AD-related phenotypes such as cognitive impairment, Aß plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of AD-related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by E22P-Aß with the toxic turn. Here, we investigated the effects of chronic treatment with E22P-Aß42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with E22P-Aß42 and LPS increased nitric oxide production and the expression of interleukin-6 (IL-6), whereas it reduced the expression of HIF-1α and HIF-3α in BV-2 microglia. The reduction of HIF-1α caused by E22P-Aß42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with E22P-Aß42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-κB). E22P-Aß42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of AD pathology.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Peptídeos beta-Amiloides/metabolismo , Microglia , Lipopolissacarídeos/toxicidade , Doenças Neuroinflamatórias , Doença de Alzheimer/metabolismo , Hipóxia
3.
J Adv Res ; 44: 185-199, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36725189

RESUMO

INTRODUCTION: Microglia and macrophages participate in hematoma clearance after intracerebral hemorrhage (ICH), thereby facilitating tissue restoration and neurological recovery. Triggering receptor expressed on myeloid cells 2 (Trem2) has been indicated as a major pathology-induced immune signaling hub on the microglial/macrophage surface. Soluble Trem2 (sTrem2), the proteolytic form of Trem2, is abundant in the body fluid and is positively correlated with the pathological process. OBJECTIVES: In the present study, we aimed to investigate the potential role of sTrem2 in hematoma resolution after ICH and to elucidate its underlying mechanisms. METHODS: We explored the biological functions of sTrem2 in the murine ICH brain by stereotaxic injection of recombinant sTrem2 protein or by adeno-associated virus-mediated expression. Erythrocyte phagocytosis was assessed using flow cytometry and immunofluorescence. Western blotting was performed to evaluate protein expression. Changes in behavior, sTrem2-induced down-stream pathway, and microglia were examined. RESULTS: sTrem2 impedes hematoma resolution and impairs functional motor and sensory recovery. Interestingly, sTrem2 bypasses full-length Trem2, negatively regulating microglial/macrophage erythrophagocytosis, and promotes an inflammatory phenotype, which is associated with reduced retromer levels and impaired recycling of the pro-erythrophagocytic receptor CD36. Rescue of retromer Vps35 abolishes the phagocytosis-inhibiting effects and lysosome-dependent CD36 degradation caused by sTrem2. CONCLUSION: These findings indicate sTrem2 as a negative factor against microglia/macrophage-mediated hematoma and related neuronal damage clearance, provide insight into the mechanisms by which erythrophagocytosis is regulated and how it may be impaired after ICH, and suggest that the anti-proteolytic activity of Trem2 can be explored for ICH therapy.


Assuntos
Hemorragia Cerebral , Linfo-Histiocitose Hemofagocítica , Animais , Camundongos , Hemorragia Cerebral/complicações , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Fagocitose/fisiologia , Macrófagos/metabolismo , Microglia/metabolismo , Microglia/patologia , Hematoma/complicações , Hematoma/metabolismo , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/metabolismo , Linfo-Histiocitose Hemofagocítica/patologia , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/farmacologia , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/farmacologia , Receptores Imunológicos/metabolismo
4.
Immun Inflamm Dis ; 11(1): e756, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705403

RESUMO

INTRODUCTION: The inflammation mediated by microglial cells plays an important role in the process of neurodegenerative diseases. Recent evidence indicates that semaphorin 7A (SEMA7A) is implicated in various neurodegenerative diseases, but whether it plays a role in Parkinson's disease (PD) remains unclear. METHODS: In this study, 1.0 mmol/L 1-methyl-4-phenylpyridinium (MPP+ )-stimulated mouse microglia (BV2) cells were used as an in vitro model of PD. The expression of SEMA7A was detected by quantitative polymerase chain reaction. Cell Counting Kit-8 and apoptosis kits were used to analyze the viability and apoptosis of BV-2 cells. The content of IL-6, IL-ß, and tumor necrosis factor-α was determined by ELISA (enzyme-linked immunosorbent assay) kit. Western blot was used to detect the protein expression level of the inducible NO synthase and cyclooxygenase-2. RESULTS: Our findings indicated that SEMA7A expression in BV2 cells was upregulated after MPP+ stimulation. Knockdown of SEMA7A promoted cell viability while it inhibited apoptosis and the expression of proinflammatory enzymes and proinflammatory cytokines. Silencing SEMA7A-induced peroxisome proliferator-activated receptor-gamma (PPAR-γ) activation and mitogen-activated protein kinase (MAPK) signaling pathway inactivation. Furthermore, a PPAR-γ inhibitor and an MAPK activator promoted the effect of MPP+ on cell viability, apoptosis, and inflammation of BV2 cells; what is more, the PPAR-γ inhibitor and MAPK activator blocked the inhibitory effect of SEMA7A downregulation on MPP+ -induced injury. CONCLUSION: In general, knockdown of SEMA7A inhibits MPP+ -induced BV2 cell apoptosis and inflammation via PPAR-γ activation and MAPK inactivation, which may provide a new therapy target for PD.


Assuntos
Proteínas Quinases Ativadas por Mitógeno , Semaforinas , Camundongos , Animais , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/farmacologia , Microglia/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , 1-Metil-4-fenilpiridínio/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Inflamação/genética , Inflamação/metabolismo , Apoptose/genética , Antígenos CD/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Semaforinas/farmacologia
5.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674945

RESUMO

The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinson's disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in α-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous α-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with α-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS/STAT3/HIF-1α axis. Our research revealed the relationships among α-synuclein, IL6ST, STAT3, and HIF-1α in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD.


Assuntos
Neuroblastoma , Doença de Parkinson , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Doenças Neuroinflamatórias , Interleucina-6/genética , Interleucina-6/metabolismo , Neuroblastoma/metabolismo , Doença de Parkinson/metabolismo , Microglia/metabolismo , Receptor gp130 de Citocina/metabolismo , Fator de Transcrição STAT3/metabolismo
6.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675113

RESUMO

Both astrocytic and microglial functions have been extensively investigated in healthy subjects and neurodegenerative diseases. For astrocytes, not only various sub-types were identified but phagocytic activity was also clarified recently and is making dramatic progress. In this review paper, we mostly focus on the functional role of astrocytes in the extracellular matrix and on interactions between reactive astrocytes and reactive microglia in normal states and in neurodegenerative diseases, because the authors feel it is necessary to elucidate the mechanisms among activated glial cells in the pathology of neurological diseases in order to pave the way for drug discovery. Finally, we will review cyclic phosphatidic acid (cPA), a naturally occurring phospholipid mediator that induces a variety of biological activities in the brain both in vivo and in vitro. We propose that cPA may serve as a novel therapeutic molecule for the treatment of brain injury and neuroinflammation.


Assuntos
Microglia , Doenças Neurodegenerativas , Humanos , Microglia/patologia , Astrócitos/patologia , Doenças Neurodegenerativas/patologia , Sistema Nervoso Central , Neuroglia , Ácidos Fosfatídicos
7.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675286

RESUMO

Microglial cells (MGs), originally derived from progenitor cells in a yolk sac during early development, are glial cells located in a physiological and pathological brain. Since the brain contains various cell types, MGs could frequently interact with different cells, such as astrocytes (ACs), pericytes (PCs), and endothelial cells (ECs). However, how microglial traits are regulated via cell-cell interactions by ACs, PCs, or ECs and how they are different depending on the contacted cell types is unclear. This study aimed to clarify these questions by coculturing MGs with ACs, PCs, or ECs using mouse brain-derived cells, and microglial phenotypic changes were investigated under culture conditions that enabled direct cell-cell contact. Our results showed that ACs or PCs dose-dependently increased the number of MG, while ECs decreased it. Microarray and gene ontology analysis showed that cell fate-related genes (e.g., cell cycle, proliferation, growth, death, and apoptosis) of MGs were altered after a cell-cell contact with ACs, PCs, and ECs. Notably, microarray analysis showed that several genes, such as gap junction protein alpha 1 (Gja1), were prominently upregulated in MGs after coincubation with ACs, PCs, or ECs, regardless of cell types. Similarly, immunohistochemistry showed that an increased Gja1 expression was observed in MGs after coincubation with ACs, PCs, or ECs. Immunofluorescent and fluorescence-activated cell sorting analysis also showed that calcein-AM was transferred into MGs after coincubation with ACs, PCs, or ECs, confirming that intercellular interactions occurred between these cells. However, while Gja1 inhibition reduced the number of MGs after coincubation with ACs and PCs, this was increased after coincubation with ECs; this indicates that ACs and PCs positively regulate microglial numbers via Gja1, while ECs decrease it. Results show that ACs, PCs, or ECs exert both common and specific cell type-dependent effects on MGs through intercellular interactions. These findings also suggest that brain microglial phenotypes are different depending on their surrounding cell types, such as ACs, PCs, or ECs.


Assuntos
Células Endoteliais , Microglia , Camundongos , Animais , Células Endoteliais/metabolismo , Encéfalo , Células Cultivadas , Astrócitos/metabolismo , Pericitos/metabolismo
8.
eNeuro ; 10(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36635245

RESUMO

Environmental enrichment (EE) is beneficial for brain development and function, but our understanding of its capacity to drive circuit repair, the underlying mechanisms, and how this might vary with age remains limited. Ten-m3 knock-out (KO) mice exhibit a dramatic and stereotyped mistargeting of ipsilateral retinal inputs to the thalamus, resulting in visual deficits. We have recently shown a previously unexpected capacity for EE during early postnatal life (from birth for six weeks) to drive the partial elimination of miswired axonal projections, along with a recovery of visually mediated behavior, but the timeline of this repair was unclear. Here, we reveal that with just 3.5 weeks of EE from birth, Ten-m3 KOs exhibit a partial behavioral rescue, accompanied by pruning of the most profoundly miswired retinogeniculate terminals. Analysis suggests that the pruning is underway at this time point, providing an ideal opportunity to probe potential mechanisms. With the shorter EE-period, we found a localized increase in microglial density and activation profile within the identified geniculate region where corrective pruning was observed. No comparable response to EE was found in age-matched wild-type (WT) mice. These findings identify microglia as a potential mechanistic link through which EE drives the elimination of miswired neural circuits during early postnatal development. Activity driven, atypical recruitment of microglia to prune aberrant connectivity and restore function may have important therapeutic implications for neurodevelopmental disorders such as autistic spectrum disorder.


Assuntos
Axônios , Microglia , Animais , Camundongos , Camundongos Knockout , Microglia/fisiologia , Plasticidade Neuronal , Retina/fisiologia , Camundongos Endogâmicos C57BL
9.
Curr Protoc ; 3(1): e638, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36622815

RESUMO

Microglia function as the tissue-specific resident macrophages of the nervous system, performing immune and non-immune functions. These functions are critical to development and to maintain homeostasis in the nervous system throughout the lifespan, and during brain injury or disease. One method by which microglia maintain homeostasis is phagocytosis of aberrant proteins, extracellular debris, synapses, or apoptotic cells. Phagocytic function can be changed by environmental or genetic risk factors that affect microglia. These protocols present a rapid and simple in vitro high-content imaging protocol for studying phagocytosis in the murine microglia BV-2 cell line. High-content imaging and analysis enable versatility of the assay, which can be used to test multiple experimental conditions, or as a screening tool. © 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. Basic Protocol 1: Phagocytosis of fluorescently labeled particles Basic Protocol 2: Examining modifications to phagocytosis by test substances Basic Protocol 3: High content imaging and analysis of phagocytic cells.


Assuntos
Microglia , Fagocitose , Camundongos , Humanos , Animais , Microglia/metabolismo , Fagocitose/fisiologia , Fagócitos , Linhagem Celular , Sinapses
10.
Cell Death Dis ; 14(1): 16, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635255

RESUMO

In multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, both resident microglia and infiltrating macrophages contribute to demyelination as well as spontaneous remyelination. Nevertheless, the specific roles of microglia versus macrophages are unknown. We investigated the influence of microglia in EAE using the colony stimulating factor 1 receptor (CSF-1R) inhibitor, PLX5622, to deplete microglial population and Ccr2RFP/+ fmsEGFP/+ mice, to distinguish blood-derived macrophages from microglia. PLX5622 treatment depleted microglia and meningeal macrophages, and provoked a massive infiltration of CCR2+ macrophages into demyelinating lesions and spinal cord parenchyma, albeit it did not alter EAE chronic phase. In contrast, microglia and meningeal macrophages depletion reduced the expression of major histocompatibility complex II and CD80 co-stimulatory molecule in dendritic cells, macrophages and microglia. In addition, it diminished T cell reactivation and proliferation in the spinal cord parenchyma, inducing a significant delay in EAE onset. Altogether, these data point to a specific role of CNS microglia and meningeal macrophages in antigen presentation and T cell reactivation at initial stages of EAE.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Microglia/metabolismo , Macrófagos/metabolismo , Esclerose Múltipla/metabolismo , Medula Espinal/patologia , Camundongos Endogâmicos C57BL
11.
Sci Rep ; 13(1): 633, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635325

RESUMO

Microglial cells are the primary resident immune cells in the retina. In healthy adults, they are ramified; that is, they have extensive processes that move continually. In adult retinas, microglia maintain the normal structure and function of neurons and other glial cells, but the mechanism underlying this process is not well-understood. In the mouse hippocampus, microglia engulf small pieces of axons and presynaptic terminals via a process called trogocytosis. Here we report that microglia in the adult macaque retina also engulf pieces of neurons and glial cells, but not at sites of synapses. We analyzed microglia in a volume of serial, ultrathin sections of central macaque retina in which many neurons that ramify in the inner plexiform layer (IPL) had been reconstructed previously. We surveyed the IPL and identified the somas of microglia by their small size and scant cytoplasm. We then reconstructed the microglia and studied their interactions with other cells. We found that ramified microglia frequently ingested small pieces of each major type of inner retinal neuron and Müller glial cells via trogocytosis. There were a few instances where the interactions took place near synapses, but the synapses, themselves, were never engulfed. If trogocytosis by retinal microglia plays a role in synaptic remodeling, it was not apparent from the ultrastructure. Instead, we propose that trogocytosis enables these microglia to present antigens derived from normal inner retinal cells and, when activated, they would promote antigen-specific tolerance.


Assuntos
Microglia , Neurônios Retinianos , Animais , Camundongos , Microglia/fisiologia , Trogocitose , Retina , Neuroglia
12.
Pharm Biol ; 61(1): 135-143, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36617895

RESUMO

CONTEXT: Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. OBJECTIVE: This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. MATERIALS AND METHODS: BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. RESULTS: HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1ß compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. DISCUSSION AND CONCLUSIONS: HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.


Assuntos
Alcaloides , Huperzia , Lipopolissacarídeos/farmacologia , Huperzia/metabolismo , Interleucina-6/metabolismo , Doenças Neuroinflamatórias , Dinoprostona/metabolismo , Microglia , Fator de Necrose Tumoral alfa/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Alcaloides/farmacologia , Alcaloides/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
13.
Open Biol ; 13(1): 220200, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36629019

RESUMO

Microglia are very sensitive to changes in the environment and respond through morphological, functional and metabolic adaptations. To depict the modifications microglia undergo under healthy and pathological conditions, we developed free access image analysis scripts to quantify microglia morphologies and phagocytosis. Neuron-glia cultures, in which microglia express the reporter tdTomato, were exposed to excitotoxicity or excitotoxicity + inflammation and analysed 8 h later. Neuronal death was assessed by SYTOX staining of nucleus debris and phagocytosis was measured through the engulfment of SYTOX+ particles in microglia. We identified seven morphologies: round, hypertrophic, fried egg, bipolar and three 'inflamed' morphologies. We generated a classifier able to separate them and assign one of the seven classes to each microglia in sample images. In control cultures, round and hypertrophic morphologies were predominant. Excitotoxicity had a limited effect on the composition of the populations. By contrast, excitotoxicity + inflammation promoted an enrichment in inflamed morphologies and increased the percentage of phagocytosing microglia. Our data suggest that inflammation is critical to promote phenotypical changes in microglia. We also validated our tools for the segmentation of microglia in brain slices and performed morphometry with the obtained mask. Our method is versatile and useful to correlate microglia sub-populations and behaviour with environmental changes.


Assuntos
Microglia , Fagocitose , Humanos , Microglia/metabolismo , Inflamação/metabolismo , Morte Celular , Neurônios/metabolismo
14.
Molecules ; 28(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36677566

RESUMO

Microglia are neuroglia in the brain with an innate immune function and participate in the progress of neurodegenerative diseases. Osthole (OST) is a coumarin derivative extracted from Cnidium monnieri and bears a microglia-antagonizing ability. However, the underlying mechanism of the antagonism is not clear. The lipopolysaccharides-induced microglial BV2 cell line and amyloid-overexpressing fruit fly were used as models to study OST treatment. We found that OST treatment is sufficient to evoke NRF2 cascade under an LPS-induced inflammatory environment, and silencing NRF2 is sufficient to abolish the process. Moreover, we found that OST is sufficient to antagonize microglial activation in both LPS-induced BV2 cells and Aß-overexpressing fruit flies, and silencing NRF2 abolishes OST's antagonism. Furthermore, OST treatment rescued survival, climbing, and the learning ability of Aß-overexpressing fruit flies and relieved oxidative stress. In conclusion, we proved that OST antagonizes microglial activation induced by either LPS or Aß and that NRF2 is necessary for OST's antagonism.


Assuntos
Cumarínicos , Microglia , Cumarínicos/farmacologia , Lipopolissacarídeos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Camundongos , Linhagem Celular , Drosophila
16.
Nutr Neurosci ; 26(2): 127-137, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36692990

RESUMO

ABSTRACTMicroglia are key regulators of inflammation and oxidative stress (OS) in the CNS. Microglia activation can lead to chronic inflammation, OS, and neurodegeneration. Blueberries (BB) reduce inflammation and OS when administered to microglia before stressors such as lipopolysaccharide (LPS), but the therapeutic value of BBs administered after activation by stressors has not been examined. Therefore, this study investigated the differential effects of pre-, post-, and pre-/post-BB on inflammation and OS in LPS-activated microglia. Rat microglia were pretreated with BB (0.5 mg/mL) or control media (C) for 24 hours, incubated overnight with LPS (0 or 200 ng/mL), and post-treated with BB or C for 24 hours. Biomarkers of inflammation (e.g. nitrite [NO2-], tumor necrosis factor-ɑ [TNFɑ], inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2], phosphorylated IκB-α [pIκB-ɑ]) and OS (e.g. NADPH oxidase [NOX2]) were assessed. LPS increased NO2-, TNFɑ, COX-2, iNOS, pIκB-ɑ, and NOX2 compared to non-stressed conditions (P < 0.05), however BB before and/or after LPS significantly reduced these markers compared to no BB (P < 0.05). Pre-BB was more effective than post-BB at reducing LPS-induced NO2-, TNFɑ, and COX-2 (P < 0.05). Pre-BB was also more effective than pre-/post-BB at attenuating LPS-induced NO2- and TNFɑ (P < 0.05). All BB treatments were equally effective in reducing LPS-induced iNOS, pIκB-ɑ, and NOX2. Results suggest that BBs can target the downstream events of LPS-induced microglial activation and prevent stressor-induced neuroinflammation and OS. Furthermore, BBs may not need to be present prior to microglial activation for beneficial effects, suggesting that dietary interventions may be effective even after initiation of disease processes.Graphical Abstract. Cascade of inflammatory and OS-inducing events associated with self-propelling microglial activation by LPS and the effects of blueberry (0.5 mg/mL) administered before and/or after LPS on these processes (blue arrows). BB, blueberry; COX2, cyclooxygenase-2; IκB-ɑ, inhibitor kappa-B-ɑ; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; NF-κB, nuclear factor kappa-B; NO, nitric oxide; NOX2, NADPH oxidase; OS, oxidative stress; ROS, reactive oxygen species; TNFɑ, tumor necrosis factor-ɑ.


Assuntos
Mirtilos Azuis (Planta) , Microglia , Ratos , Animais , Transdução de Sinais , Lipopolissacarídeos/farmacologia , Inibidor de NF-kappaB alfa/farmacologia , Inibidor de NF-kappaB alfa/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Dióxido de Nitrogênio/efeitos adversos , NF-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Inflamação/tratamento farmacológico , NADPH Oxidases/metabolismo , NADPH Oxidases/farmacologia , NADPH Oxidases/uso terapêutico , Estresse Oxidativo , Óxido Nítrico/metabolismo
17.
Neural Plast ; 2023: 4637073, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644710

RESUMO

CX3CR1 is a G protein-coupled receptor that is expressed exclusively by microglia within the brain parenchyma. The only known physiological CX3CR1 ligand is the chemokine fractalkine (FKN), which is constitutively expressed in neuronal cell membranes and tonically released by them. Through its key role in microglia-neuron communication, the FKN/CX3CR1 axis regulates microglial state, neuronal survival, synaptic plasticity, and a variety of synaptic functions, as well as neuronal excitability via cytokine release modulation, chemotaxis, and phagocytosis. Thus, the absence of CX3CR1 or any failure in the FKN/CX3CR1 axis has been linked to alterations in different brain functions, including changes in synaptic and network plasticity in structures such as the hippocampus, cortex, brainstem, and spinal cord. Since synaptic plasticity is a basic phenomenon in neural circuit integration and adjustment, here, we will review its modulation by the FKN/CX3CR1 axis in diverse brain circuits and its impact on brain function and adaptation in health and disease.


Assuntos
Sistema Nervoso Central , Quimiocina CX3CL1 , Quimiocina CX3CL1/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Microglia/metabolismo , Medula Espinal/metabolismo
18.
Neuron ; 111(1): 1-2, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36603547

RESUMO

Classically, microglia recognize and internalize amyloid-ß (Aß) via it binding to cell surface receptors. In this issue of Neuron, Hu et al.1 report that microglia "feel" and internalize Aß plaques using the stiffness-sensing channel Piezo1. This could allow new approaches to treating Alzheimer's disease.


Assuntos
Doença de Alzheimer , Microglia , Humanos , Animais , Camundongos , Microglia/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Receptores de Superfície Celular/metabolismo , Emoções , Placa Amiloide/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , Canais Iônicos/metabolismo
19.
Neuron ; 111(2): 142-144, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36657395

RESUMO

The ApoE-Trem2 pathway links two of the most important genetic risk variants for sporadic Alzheimer's disease. In this issue of Neuron, Gratuze and colleagues1 report that Trem2 deficiency further aggravates neurodegeneration in tau mutant mice expressing human ApoE4. Together with previous work, this study points to a complex interaction and highlights the need for studying molecular interactions on all human ApoE variants.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Fagocitose , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Camundongos Transgênicos
20.
J Clin Invest ; 133(1)2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36594466

RESUMO

Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Microglia/patologia , Glioblastoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Macrófagos/patologia , Sistema Nervoso Central/patologia , Microambiente Tumoral
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