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2.
Zhen Ci Yan Jiu ; 46(9): 769-74, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34558243

RESUMO

OBJECTIVE: To observe the effect of moxibustion at myofascial trigger points on microglia activation and the expression of brain-derived neurotrophic factor (BDNF) in the spinal cord of rats with myofascial pain syndrome (MPS), so as to explore the central mechanism of the analgesic effect of moxibustion. METHODS: Twenty-four male SD rats were randomly divi-ded into control, model and moxibustion groups (n=8 in each group). The MPS model was established by strinking on fascia musculares and eccentric exercise. Rats in the moxibustion group were treated with mild moxibustion at myofascial trigger point for 15 min, once daily for 7 days. The thermal withdrawal latency (TWL) of rats was measured with a hot stabbing instrument. The pathological changes of the rat medial femoris muscle were observed after H.E. staining. The expressions of microglia marker (OX-42) and BDNF in the spinal dorsal horn were detected by immunohistochemistry and Western blot, separately. RESULTS: After modeling, the TWL of both the model and the moxibustion groups were significantly down-regulated (P<0.01),and were significantly decreased in contrast to that of the control group (P<0.01). After treatment and compared with the model group, the TWL of the moxibustion group was significantly increased (P<0.01) in the moxibustion group. Rat's muscle fibers of the control group were uniform in thickness and arranged tightly and regularly. While in the model group, some fractures and connective structure tissue renewal, irregular arrangement, and inflammatory cell infiltration were seen. The morphology of muscle fibers in the moxibustion group was close to normal, and the arrangement was neat and orderly, with a small amount of inflammatory cell infiltration. Compared with the control group, the expression of OX-42 and BDNF in the spinal dorsal horn of rats in the model group was increased(P<0.01). Following the treatment, and in comparison with the model group, the expression of OX-42 and BDNF of moxibustion group was down-regulated(P<0.05). CONCLUSION: Moxibustion can significantly improve the injury of the medial femoral muscle and the TWL in MPS rats,which may be related to its effects in inhibiting the activation of spinal dorsal horn microglia and reducing the expression of BDNF.


Assuntos
Moxibustão , Síndromes da Dor Miofascial , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Masculino , Microglia , Ratos , Ratos Sprague-Dawley , Medula Espinal
3.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(9): 775-780, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34533123

RESUMO

Objective To investigate the effect of necrostatin-1 on locomotor recovery after spinal cord injury (SCI) in mice, and to explore the role of apoptosis and M1 type-microglia/macrophage-mediated pro-inflammation in the protective effect. Methods Male C57BL/6 mice were randomly divided into four groups: control group, necrostatin-1 group, SCI model group, necrostatin-1-treated group after SCI, with 20 mice in each. For SCI model group, mice were anesthetized with 10 g/L pentobarbital sodium with a dose of 8 mL/kg. After skin disinfection, T8 laminectomy was performed under operating microscope, and the T8 spinal cord was clearly revealed. The injury model was established with a device designed by our own with the parameter at 0.2 mm-width for 20 seconds. Manual urination was performed once a day. For necrostatin-1-treated group after SCI, 7.8 mg/kg of necrostatin-1 was intravenously administrated at the 1, 2, and 3 days after SCI. For necrostatin-1 group, necrostatin-1 was intravenously injected for three days. Basso Mouse Scale(BMS) score and standardized rump-height index were used to evaluate locomotor function at 1-, 3-, 5-, 7-, 10- and 14-day after injury. To observe cell apoptosis in injured cord, TUNEL staining was performed at 1-, 3-, 7-, and 14-day after injury. Western blot and immunohistochemical staining were performed to detect the expression of inducible nitric oxide synthase (iNOS), a classical marker of M1 type microglia/macrophage. Real time quantitative PCR was used to detect mRNA levels of TNF-α, interleukin-1ß (IL-1ß), IL-18, IL-4, IL-5, and IL-10. Results Necrostatin-1 significantly promoted the locomotor recovery in mice after SCI, reduced cell apoptosis around the SCI area; decreased the protein expression of M1 type microglia/macrophage marker iNOS and the number of iNOS-positive microglia/macrophage, and down-regulated the transcription levels of pro-inflammatory cytokines TNF-α, IL-18, and IL-1ß, while promoting the transcription of anti-inflammatory cytokines IL-4, IL-5, and IL-10. Conclusion Necrostatin-1 significantly promotes locomotor function recovery after SCI in mice by reducing the number of apoptotic cells and inhibiting M1 microglia/macrophages-mediated pro-inflammatory factors.


Assuntos
Microglia , Traumatismos da Medula Espinal , Animais , Apoptose , Imidazóis , Indóis , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico
4.
Nat Commun ; 12(1): 5289, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489419

RESUMO

Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12-/- and PANX1-/- mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.


Assuntos
Encéfalo/irrigação sanguínea , Conexinas/genética , Microglia/metabolismo , Células Mieloides/metabolismo , Proteínas do Tecido Nervoso/genética , Receptores Purinérgicos P2Y12/genética , Animais , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Contagem de Células , Circulação Cerebrovascular/fisiologia , Conexinas/deficiência , Eletrodos Implantados , Feminino , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microglia/citologia , Células Mieloides/citologia , Proteínas do Tecido Nervoso/deficiência , Neuroimagem/instrumentação , Neuroimagem/métodos , Receptores Purinérgicos P2Y12/deficiência , Receptores Purinérgicos P2Y12/metabolismo , Vasodilatação/fisiologia
5.
Ecotoxicol Environ Saf ; 225: 112725, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34492628

RESUMO

Despite the wide application of cobalt nanoparticles (CoNPs), its neurotoxicity and the underlying mechanisms are not fully understood. In this study, CoNPs-induced toxic effect was examined in both C57BL/6J mice and microglial BV2 cells. CoNPs-induced brain weight loss and the reduction of Nissl bodies, assuring neural damage. Moreover, both total unphosphorylated Tau and phosphorylated Tau (pTau; T231 and S262) expressions in the hippocampus and cortex were upregulated, unveiling Tau phosphorylation. Besides, the increase in inflammation-related proteins NLRP3 and IL-1ß were found in mice brain. Corroborating that, microglial marker Iba-1 expression was also increased, suggesting microglia-involved inflammation. Among the NADPH oxidase (NOX) family proteins tested, only NOX2 was activated by CoNPs in hippocampus. Therefore, BV2 cells were employed to further investigate the role of NOX2. In BV2 cells, NOX2 expression was upregulated, corresponding to the production of ROS. Moreover, similar induction in Tau phosphorylation and inflammation-related protein expressions were observed in CoNPs-exposed BV2 cells. Treatment of apocynin, a NOX2 inhibitor, reduced ROS generation and reversed Tau phosphorylation and inflammation caused by CoNPs. Thus, CoNPs induced ROS production, Tau phosphorylation and inflammation specially via NOX2 activation.


Assuntos
Microglia , Nanopartículas , Animais , Cobalto , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação
6.
Ecotoxicol Environ Saf ; 225: 112806, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34555716

RESUMO

Ionic liquids (ILs) are widely used for their physical and chemical properties. Toxicological assessments of ILs could help to avoid their threat to human health, but these are rarely reported, and no assessments of IL neurotoxicity in mammals have been performed. Here, we aimed to evaluate the neurotoxicity of chronic 1-octyl-3-methylimidazolium hexafluorophosphate ([C8mim][PF6]) (0, 1 mg/kg) exposure during development on rats. Our results indicated that chronic exposure to low-dose ([C8mim][PF6]) induces behavioural abnormalities, including cognitive deficits, social communication disorders, and sensory gating function impairment. Moreover, rats subjected to chronic ([C8mim][PF6]) exposure showed hypofunction of glutamatergic excitatory synapses, including increased expression of NMDA receptor subunits, increased density and immaturity of dendritic spines, and increased expression of PSD95. Additionally, ([C8mim][PF6]) exposure resulted in hippocampal-specific inflammatory activation, indicated by increased levels of proinflammatory factors, elevated nuclear localisation of NF-κB, and activation of microglia and astrocytes. In conclusion, chronic exposure to low-dose ([C8mim][PF6]) induced neurotoxicity, including damage to glutamatergic excitatory synapses and inflammatory activation, which may illuminate the associated behavioural abnormalities. The results presented here may be helpful for the safe use of ILs in the future.


Assuntos
Disfunção Cognitiva , Síndromes Neurotóxicas , Animais , Astrócitos , Microglia , NF-kappa B , Síndromes Neurotóxicas/etiologia , Ratos
7.
Fitoterapia ; 154: 105029, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34506872

RESUMO

Four new chalchonoid trimers, named cochinchinenins N-Q (1-4), along with a pair of known enantiomers (5-6), were isolated from the total phenolic extract of Chinese dragon's blood (the red resin of Dracaena cochinchinensis). The planar structures of 1-4 were elucidated by extensive spectroscopic analysis including HRESIMS and 1D/2D NMR. The absolute configurations of new compounds were established by ECD data. Compound 1 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 value of 11.5 ± 1.7 µM.


Assuntos
Chalconas/farmacologia , Dracaena/química , Microglia/efeitos dos fármacos , Extratos Vegetais/química , Animais , Linhagem Celular , Chalconas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Óxido Nítrico , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Resinas Vegetais/química
8.
Nat Commun ; 12(1): 5369, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508095

RESUMO

Deep neural networks (DNNs) capture complex relationships among variables, however, because they require copious samples, their potential has yet to be fully tapped for understanding relationships between gene expression and human phenotypes. Here we introduce an analysis framework, namely MD-AD (Multi-task Deep learning for Alzheimer's Disease neuropathology), which leverages an unexpected synergy between DNNs and multi-cohort settings. In these settings, true joint analysis can be stymied using conventional statistical methods, which require "harmonized" phenotypes and tend to capture cohort-level variations, obscuring subtler true disease signals. Instead, MD-AD incorporates related phenotypes sparsely measured across cohorts, and learns interactions between genes and phenotypes not discovered using linear models, identifying subtler signals than cohort-level variations which can be uniquely recapitulated in animal models and across tissues. We show that MD-AD exploits sex-specific relationships between microglial immune response and neuropathology, providing a nuanced context for the association between inflammatory genes and Alzheimer's Disease.


Assuntos
Doença de Alzheimer/genética , Encéfalo/patologia , Aprendizado Profundo , Regulação da Expressão Gênica/imunologia , Microglia/imunologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Animais , Encéfalo/citologia , Encéfalo/imunologia , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Camundongos , Microglia/patologia , RNA-Seq , Fatores Sexuais
9.
Nat Commun ; 12(1): 5382, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508096

RESUMO

Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase the association between TLR2 and MyD88, resulting in microglial activation. The TLR2-interaction domain of MyD88 (wtTIDM) peptide-mediated selective inhibition of TLR2 reduces PFF-induced microglial inflammation in vitro. In PFF-seeded A53T mice, the nasal administration of the wtTIDM peptide, NEMO-binding domain (wtNBD) peptide, or genetic deletion of TLR2 reduces glial inflammation, decreases α-syn spreading, and protects dopaminergic neurons by inhibiting NF-κB. In summary, α-syn spreading depends on the TLR2/MyD88/NF-κB pathway and it can be reduced by nasal delivery of wtTIDM and wtNBD peptides.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Microglia/patologia , alfa-Sinucleína/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Humanos , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Camundongos , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Mutagênese Sítio-Dirigida , Mutação , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Cultura Primária de Células , Regiões Promotoras Genéticas , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , alfa-Sinucleína/genética
10.
Transl Psychiatry ; 11(1): 490, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556640

RESUMO

Changes in immune function are associated with variance in cognitive functioning in schizophrenia. Given that microglia are the primary innate immune cells in the brain, we examined whether schizophrenia risk-associated microglial genes (measured via polygenic score analysis) explained variation in cognition in patients with schizophrenia and controls (n = 1,238) and tested whether grey matter mediated this association. We further sought to replicate these associations in an independent sample of UK Biobank participants (n = 134,827). We then compared the strength of these microglial associations to that of neuronal and astroglial (i.e., other brain-expressed genes) polygenic scores, and used MAGMA to test for enrichment of these gene-sets with schizophrenia risk. Increased microglial schizophrenia polygenic risk was associated with significantly lower performance across several measures of cognitive functioning in both samples; associations which were then found to be mediated via total grey matter volume in the UK Biobank. Unlike neuronal genes which did show evidence of enrichment, the microglial gene-set was not significantly enriched for schizophrenia, suggesting that the relevance of microglia may be for neurodevelopmental processes related more generally to cognition. Further, the microglial polygenic score was associated with performance on a range of cognitive measures in a manner comparable to the neuronal schizophrenia polygenic score, with fewer cognitive associations observed for the astroglial score. In conclusion, our study supports the growing evidence of the importance of immune processes to understanding cognition and brain structure in both patients and in the healthy population.


Assuntos
Microglia , Esquizofrenia , Encéfalo/diagnóstico por imagem , Cognição , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Esquizofrenia/genética
11.
Nat Commun ; 12(1): 5659, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580300

RESUMO

Early Alzheimer's disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy ß-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.


Assuntos
Doença de Alzheimer/complicações , Córtex Cerebral/patologia , Disfunção Cognitiva/imunologia , Redes Reguladoras de Genes/imunologia , Hidrocefalia de Pressão Normal/imunologia , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Astrócitos/imunologia , Astrócitos/patologia , Biópsia , Córtex Cerebral/citologia , Córtex Cerebral/imunologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Feminino , Humanos , Hidrocefalia de Pressão Normal/genética , Hidrocefalia de Pressão Normal/patologia , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Microglia/imunologia , Microglia/patologia , Testes Neuropsicológicos , RNA-Seq , Estudos Retrospectivos
12.
J Vis Exp ; (175)2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34570103

RESUMO

Glial cells probably have a considerable implication in the pathophysiology of neurodegenerative disorders, such as Alzheimer's disease (AD). Their alterations are perhaps associated with a pro-inflammatory state. The TgF344-AD rat strain has been designed to express human APP and human PS1ΔE9 genes, encoding for amyloid proteins Aß-40 and Aß-42 and displays amyloid pathology and cognitive deficits with aging. The TgF344-AD rat model is used in this study to evaluate the cellular origin of the 18 kDa translocator protein (TSPO, a marker of glial cell activation) binding, and the 5HT2A-receptor (5HT2AR) serotonin receptor levels that are possibly disrupted in AD. The technique presented here is Fluorescence-Activated Cell Sorting to Radioligand Treated Tissue (FACS-RTT), a quantitative cell-type-specific technique complementary to in vivo PET or SPECT or ex vivo/in vitro autoradiography techniques. It quantifies the same radiolabeled tracer used prior for imaging, using a γ counter after cytometry cell sorting. This allows determining the cellular origin of the radiolabeled protein with high cellular specificity and sensitivity. For example, studies with FACS-RTT showed that (i) the increase in TSPO binding was associated with microglia in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation, (ii) an increase in TSPO binding at 12- and 18-months was associated with astrocytes first, and then microglia in the TgF344-AD rats compared to wild type (WT) rats, and (iii) the striatal density of 5HT2AR decreases in astrocytes at 18 months in the same rat AD model. Interestingly, this technique can be extended to virtually all radiotracers.


Assuntos
Doença de Alzheimer , Tomografia por Emissão de Pósitrons , Animais , Astrócitos , Modelos Animais de Doenças , Citometria de Fluxo , Microglia , Ratos
13.
Front Immunol ; 12: 621090, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34566948

RESUMO

Viral encephalitis is a major cause of morbidity and mortality, but the manifestation of disease varies greatly between individuals even in response to the same virus. Microglia are professional antigen presenting cells that reside in the central nervous system (CNS) parenchyma that are poised to respond to viral insults. However, the role of microglia in initiating and coordinating the antiviral response is not completely understood. Utilizing Theiler's murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, and PLX5622, a small molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R) signaling that can deplete microglia in the CNS; we investigated the role of the CSF1R-microglia axis in neurotropic picornavirus infection of C57BL/6J and SJL/J mice. These mouse strains differ in their ability to clear TMEV and exhibit different neurological disease in response to TMEV infection. CSF1R antagonism in C57BL/6J mice, which normally clear TMEV in the CNS, led to acute fatal encephalitis. In contrast, CSF1R antagonism in SJL/J mice, which normally develop a chronic CNS TMEV infection, did not result in acute encephalitis, but exacerbated TMEV-induced demyelination. Immunologically, inhibition of CSF1R in C57BL/6J mice reduced major histocompatibility complex II expression in microglia, decreased the proportion of regulatory T cells in the CNS, and upregulated proinflammatory pathways in CNS T cells. Acute CSF1R inhibition in SJL/J mice had no effect on microglial MHC-II expression and upregulated anti-inflammatory pathways in CNS T cells, however chronic CSF1R inhibition resulted in broad immunosuppression. Our results demonstrate strain-specific effects of the CSF1R-microglia axis in the context of neurotropic viral infection as well as inherent differences in microglial antigen presentation and subsequent T cell crosstalk that contribute to susceptibility to neurotropic picornavirus infection.


Assuntos
Infecções por Cardiovirus/imunologia , Microglia/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Compostos Orgânicos/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Theilovirus/imunologia
14.
Front Immunol ; 12: 646043, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34566949

RESUMO

Background: Microglia safeguard the CNS against injuries and pathogens, and in the presence of certain harmful stimuli are capable of inducing a disease-dependent inflammatory response. When exposed to anti-inflammatory cytokines, however, these cells possess the ability to switch from an inflammatory to an immunosuppressive phenotype. Cancer cells exploit this property to evade the immune system, and elicit an anti-inflammatory microenvironment that facilitates tumor attachment and growth. Objective: The tumor-supportive biological processes that are activated in microglia cells in response to anti-inflammatory cytokines released from cancer cells were explored with mass spectrometry and proteomic technologies. Methods: Serum-depleted and non-depleted human microglia cells (HMC3) were treated with a cocktail of IL-4, IL-13, IL-10, TGFß, and CCL2. The cellular protein extracts were analyzed by LC-MS/MS. Using functional annotation clustering tools, statistically significant proteins that displayed a change in abundance between cytokine-treated and non-treated cells were mapped to their biological networks and pathways. Results: The proteomic analysis of HMC3 cells enabled the identification of ~10,000 proteins. Stimulation with anti-inflammatory cytokines resulted in the activation of distinct, yet integrated clusters of proteins that trigger downstream a number of tumor-promoting biological processes. The observed changes could be classified into four major categories, i.e., mitochondrial gene expression, ECM remodeling, immune response, and impaired cell cycle progression. Intracellular immune activation was mediated mainly by the transducers of MAPK, STAT, TGFß, NFKB, and integrin signaling pathways. Abundant collagen formation along with the expression of additional receptors, matrix components, growth factors, proteases and protease inhibitors, was indicative of ECM remodeling processes supportive of cell-cell and cell-matrix adhesion. Overexpression of integrins and their modulators was reflective of signaling processes that link ECM reorganization with cytoskeletal re-arrangements supportive of cell migration. Antigen processing/presentation was represented by HLA class I histocompatibility antigens, and correlated with upregulated proteasomal subunits, vesicular/viral transport, and secretory processes. Immunosuppressive and proangiogenic chemokines, as well as anti-angiogenic factors, were detectable in low abundance. Pronounced pro-inflammatory, chemotactic or phagocytic trends were not observed, however, the expression of certain receptors, signaling and ECM proteins indicated the presence of such capabilities. Conclusions: Comprehensive proteomic profiling of HMC3 cells stimulated with anti-inflammatory cytokines revealed a spectrum of microglia phenotypes supportive of cancer development in the brain via microenvironment-dependent biological mechanisms.


Assuntos
Encéfalo/imunologia , Citocinas/imunologia , Microglia/imunologia , Proteômica/métodos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Linhagem Celular , Humanos
15.
Nat Genet ; 53(9): 1276-1282, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34493870

RESUMO

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Microglia/citologia , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/metabolismo , Proteólise , Tamanho da Amostra
17.
Transl Psychiatry ; 11(1): 461, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489395

RESUMO

Running exercise has been shown to relieve symptoms of depression, but the mechanisms underlying the antidepressant effects are unclear. Microglia and concomitant dysregulated neuroinflammation play a pivotal role in the pathogenesis of depression. However, the effects of running exercise on hippocampal neuroinflammation and the number and activation of microglia in depression have not been studied. In this study, rats were subjected to chronic unpredictable stress (CUS) for 5 weeks followed by treadmill running for 6 weeks. The depressive-like symptoms of the rats were assessed with a sucrose preference test (SPT). Immunohistochemistry and stereology were performed to quantify the total number of ionized calcium-binding adapter molecule 1 (Iba1)+ microglia, and immunofluorescence was used to quantify the density of Iba1+/cluster of differentiation 68 (CD68)+ in subregions of the hippocampus. The levels of proinflammatory cytokines in the hippocampus were measured by qRT-PCR and ELISA. The results showed that running exercise reversed the decreased sucrose preference of rats with CUS-induced depression. In addition, CUS increased the number of hippocampal microglia and microglial activation in rats, but running exercise attenuated the CUS-induced increases in the number of microglia in the hippocampus and microglial activation in the dentate gyrus (DG) of the hippocampus. Furthermore, CUS significantly increased the hippocampal levels of inflammatory factors, and the increases in inflammatory factors in the hippocampus were suppressed by running exercise. These results suggest that the antidepressant effects of exercise may be mediated by reducing the number of microglia and inhibiting microglial activation and neuroinflammation in the hippocampus.


Assuntos
Depressão , Microglia , Animais , Antidepressivos , Depressão/terapia , Modelos Animais de Doenças , Hipocampo , Ratos , Estresse Psicológico
18.
Nat Commun ; 12(1): 5219, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471138

RESUMO

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct site of interaction between microglia and axons, in both mouse and human tissues. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglia-node interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Altered axonal K+ flux following demyelination impairs the switch towards a pro-regenerative microglia phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron interaction, that may participate in microglia-neuron communication mediating pro-remyelinating effect of microglia after myelin injury.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Potássio/metabolismo , Nós Neurofibrosos/fisiologia , Remielinização/fisiologia , Animais , Axônios , Encéfalo , Receptor 1 de Quimiocina CX3C , Sistema Nervoso Central , Doenças Desmielinizantes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla , Bainha de Mielina/fisiologia , Neuroproteção
19.
Chem Biol Interact ; 348: 109653, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34516974

RESUMO

Angiotensin II, the effector peptide of the renin-angiotensin system, is not only a pivotal peptide implicated in the regulation of blood pressure but also a key mediator of the inflammatory processes that play an important role in the pathology of hypertension-related cSVD. Harpagide is the major bioactive constituent of Scrophulariae Radix widely used in traditional Chinese medicine for numerous diseases including hypertension. The present study aimed to investigate the effect of harpagide on Ang II-induced neuroinflammation and the potential mechanism. Pretreated with harpagide or resatorvid (the TLR4 pathway inhibitor), BV2 cells were treated with Ang II or LPS (the TLR4 activator). NO, pro-inflammatory cytokines, the proteins on TLR4/MyD88/NF-κB signaling pathway and the expression of CD86, CD206, TREM2 in BV2 cells were detected respectively. Subsequently, the effects of harpagide on neurotoxicity and BBB destruction triggered by Ang II-induced neuroinflammation were investigated in the co-cultures of BV2 microglia/HT22 hippocampal neurons, BV2 microglia/bEnd.3 endotheliocyte and BV2 microglia/BBB monolayer model. We found that Ang II converted microglia into M1 state and resulted in neuroinflammation through activating TLR4/MyD88/NF-κB signaling pathway. It also triggered the imbalance of TLR4/TREM2 in microglia. Ang II-mediated inflammation microglia further led to neuronal apoptosis and BBB damage. Harpagide showed the effect of alleviating Ang II-mediated neuroinflammation as well as the resulting neurotoxicity and BBB destruction through inhibiting the TLR4/MyD88/NF-κB pathway. The anti-inflammatory and neuroprotective effect of harpagide suggested that it might be a potential therapeutic strategy in hypertensive cSVD.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Glicosídeos Iridoides/farmacologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular , Humanos , Microglia/citologia , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptor 4 Toll-Like/metabolismo
20.
Front Immunol ; 12: 650176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512619

RESUMO

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans. Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Complicações do Diabetes/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Pantoea/química , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais
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