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1.
J Gen Virol ; 102(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34704923

RESUMO

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Assuntos
Encéfalo/patologia , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/virologia , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Humanos , Inflamação , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Microglia/patologia
2.
Nat Commun ; 12(1): 5916, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625548

RESUMO

Microglia are brain resident macrophages that play vital roles in central nervous system (CNS) development, homeostasis, and pathology. Microglia both remodel synapses and engulf apoptotic cell corpses during development, but whether unique molecular programs regulate these distinct phagocytic functions is unknown. Here we identify a molecularly distinct microglial subset in the synapse rich regions of the zebrafish (Danio rerio) brain. We found that ramified microglia increased in synaptic regions of the midbrain and hindbrain between 7 and 28 days post fertilization. In contrast, microglia in the optic tectum were ameboid and clustered around neurogenic zones. Using single-cell mRNA sequencing combined with metadata from regional bulk sequencing, we identified synaptic-region associated microglia (SAMs) that were highly enriched in the hindbrain and expressed multiple candidate synapse modulating genes, including genes in the complement pathway. In contrast, neurogenic associated microglia (NAMs) were enriched in the optic tectum, had active cathepsin activity, and preferentially engulfed neuronal corpses. These data reveal that molecularly distinct phagocytic programs mediate synaptic remodeling and cell engulfment, and establish the zebrafish hindbrain as a model for investigating microglial-synapse interactions.


Assuntos
Mesencéfalo/citologia , Microglia/citologia , Neurogênese/genética , Rombencéfalo/citologia , Colículos Superiores/citologia , Transcriptoma , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/imunologia , Catepsina B/genética , Catepsina B/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/imunologia , Microglia/imunologia , Neurogênese/imunologia , Neurônios/citologia , Neurônios/imunologia , Fagocitose , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/imunologia , Análise de Célula Única , Colículos Superiores/crescimento & desenvolvimento , Colículos Superiores/imunologia , Sinapses/imunologia , Sinapses/metabolismo , Sinapses/ultraestrutura , Peixe-Zebra , Proteínas de Peixe-Zebra/imunologia
3.
Front Immunol ; 12: 689453, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616393

RESUMO

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.


Assuntos
Alcoolismo/metabolismo , Sistema Límbico/metabolismo , Microglia/metabolismo , Neuroimunomodulação , Dor/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores Opioides mu/metabolismo , Abstinência de Álcool , Alcoolismo/imunologia , Alcoolismo/fisiopatologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Adjuvante de Freund , Mediadores da Inflamação/metabolismo , Sistema Límbico/imunologia , Sistema Límbico/fisiopatologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/imunologia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Dor/induzido quimicamente , Dor/imunologia , Dor/fisiopatologia , Fosforilação , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiopatologia , Ratos Sprague-Dawley , Recidiva , Fatores Sexuais
4.
Front Immunol ; 12: 730088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484241

RESUMO

In December 2019, a new viral disease emerged and quickly spread all around the world. In March 2020, the COVID-19 outbreak was classified as a global pandemic and by June 2021, the number of infected people grew to over 170 million. Along with the patients' mild-to-severe respiratory symptoms, reports on probable central nervous system (CNS) effects appeared shortly, raising concerns about the possible long-term detrimental effects on human cognition. It remains unresolved whether the neurological symptoms are caused directly by the SARS-CoV-2 infiltration in the brain, indirectly by secondary immune effects of a cytokine storm and antibody overproduction, or as a consequence of systemic hypoxia-mediated microglia activation. In severe COVID-19 cases with impaired lung capacity, hypoxia is an anticipated subsidiary event that can cause progressive and irreversible damage to neurons. To resolve this problem, intensive research is currently ongoing, which seeks to evaluate the SARS-CoV-2 virus' neuroinvasive potential and the examination of the antibody and autoantibody generation upon infection, as well as the effects of prolonged systemic hypoxia on the CNS. In this review, we summarize the current research on the possible interplay of the SARS-CoV-2 effects on the lung, especially on alveolar macrophages and direct and indirect effects on the brain, with special emphasis on microglia, as a possible culprit of neurological manifestation during COVID-19.


Assuntos
COVID-19/complicações , Infecções do Sistema Nervoso Central/complicações , Infecções do Sistema Nervoso Central/virologia , Pulmão/virologia , SARS-CoV-2/patogenicidade , COVID-19/imunologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Humanos , Pulmão/imunologia , Microglia/imunologia , Microglia/patologia , Microglia/virologia , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/imunologia
5.
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
6.
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
7.
Front Immunol ; 12: 687898, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484185

RESUMO

Inflammation after acute CNS injury plays a dual role. The interplay between immune cells and inflammatory mediators is critical to the outcome of injured neurons. Microglia/macrophages are the first sensors and regulators of the immune response. We previously found that the enhancement of macrophages on neuron survival does not persist in thymectomized rats. How T lymphocytes and macrophages interact and benefit neuron survival is not fully elucidated. To this point, we introduce and characterize a cell-retina co-culture model that mimics the recruitment of peripheral lymphocytes at the injury site. Three-day post-optic nerve transection (ONT) in Fischer 344 rats, transected retinas were co-cultured with either peripheral lymph node-derived lymphocytes (injury-activated) or from intact rats as the control. The injury-activated lymphocytes preserved retinal ganglion cells (RGCs) and caused extensive retina microglial/macrophage infiltration. CD4+CD25+ T cells were upregulated in the injury-activated lymphocytes and increased RGC survival, suggesting that CD4+CD25+ T cells suppressed the cytotoxicity of control lymphocytes. When microglia/macrophages were depleted by clodronate, neuron loss was more extensive, the cytotoxicity of control lymphocytes on RGCs was alleviated, and the neuroprotective effect of injury-activated lymphocytes remain unchanged Cytokine detection showed an increase in IL-6 and TNF-α levels that were reduced with microglia/macrophage depletion. Our results suggest that microglial/macrophage infiltration into axotomized retinas promotes RGC survival by secreting cytokines to induce CD4+CD25+ T cells and suppress T cell-mediated RGC toxicity. These findings reveal a specific role for microglia/macrophage and CD4+CD25+ T cells in inflammation after CNS injury, thereby adding to the mechanistic basis for the development of microglial/macrophage modulation therapy for traumatic CNS injury.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Macrófagos/imunologia , Microglia/imunologia , Traumatismos do Nervo Óptico/imunologia , Células Ganglionares da Retina/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular , Sobrevivência Celular , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-6/metabolismo , Linfonodos/metabolismo , Macrófagos/metabolismo , Masculino , Microglia/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Ratos Endogâmicos F344 , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/metabolismo
8.
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
9.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575917

RESUMO

Multiple sclerosis (MS) has been clinically considered a chronic inflammatory disease of the white matter; however, in the last decade growing evidence supported an important role of gray matter pathology as a major contributor of MS-related disability and the involvement of synaptic structures assumed a key role in the pathophysiology of the disease. Synaptic contacts are considered central units in the information flow, involved in synaptic transmission and plasticity, critical processes for the shaping and functioning of brain networks. During the course of MS, the immune system and its diffusible mediators interact with synaptic structures leading to changes in their structure and function, influencing brain network dynamics. The purpose of this review is to provide an overview of the existing literature on synaptic involvement during experimental and human MS, in order to understand the mechanisms by which synaptic failure eventually leads to brain networks alterations and contributes to disabling MS symptoms and disease progression.


Assuntos
Suscetibilidade a Doenças , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Animais , Biomarcadores , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental , Humanos , Inflamação , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/diagnóstico
10.
Front Immunol ; 12: 667705, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489926

RESUMO

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS). Besides the vital role of T cells, other immune cells, including B cells, innate immune cells, and macrophages (MФs), also play a critical role in MS pathogenesis. Tissue-resident MФs in the brain's parenchyma, known as microglia and monocyte-derived MФs, enter into the CNS following alterations in CNS homeostasis that induce inflammatory responses in MS. Although the neuroprotective and anti-inflammatory actions of monocyte-derived MФs and resident MФs are required to maintain CNS tolerance, they can release inflammatory cytokines and reactivate primed T cells during neuroinflammation. In the CNS of MS patients, elevated myeloid cells and activated MФs have been found and associated with demyelination and axonal loss. Thus, according to the role of MФs in neuroinflammation, they have attracted attention as a therapeutic target. Also, due to their different origin, location, and turnover, other strategies may require to target the various myeloid cell populations. Here we review the role of distinct subsets of MФs in the pathogenesis of MS and different therapeutic agents that target these cells.


Assuntos
Anti-Inflamatórios/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Animais , Anti-Inflamatórios/efeitos adversos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Humanos , Fatores Imunológicos/efeitos adversos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Fenótipo , Transdução de Sinais
11.
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
12.
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
13.
Cells ; 10(9)2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34572030

RESUMO

Microglia, the innate immune cells of the central nervous system, play a pivotal role in the modulation of neuroinflammation. Neuroinflammation has been implicated in many diseases of the CNS, including Alzheimer's disease and Parkinson's disease. It is well documented that microglial activation, initiated by a variety of stressors, can trigger a potentially destructive neuroinflammatory response via the release of pro-inflammatory molecules, and reactive oxygen and nitrogen species. However, the potential anti-inflammatory and neuroprotective effects that microglia are also thought to exhibit have been under-investigated. The application of ionising radiation at different doses and dose schedules may reveal novel methods for the control of microglial response to stressors, potentially highlighting avenues for treatment of neuroinflammation associated CNS disorders, such as Alzheimer's disease and Parkinson's disease. There remains a need to characterise the response of microglia to radiation, particularly low dose ionising radiation.


Assuntos
Mediadores da Inflamação/metabolismo , Microglia/efeitos da radiação , Doenças Neurodegenerativas/radioterapia , Neuroimunomodulação/efeitos da radiação , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Relação Dose-Resposta à Radiação , Humanos , Imunidade Inata/efeitos da radiação , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Nitrosativo/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Fenótipo , Receptores de GABA/metabolismo
14.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360004

RESUMO

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Assuntos
Envelhecimento , Encéfalo/fisiopatologia , Inflamação/fisiopatologia , Microglia/virologia , Viroses/fisiopatologia , Animais , Encéfalo/imunologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Microglia/imunologia , Microglia/patologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Viroses/virologia
15.
Front Immunol ; 12: 650105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394072

RESUMO

Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.


Assuntos
Neoplasias Encefálicas/imunologia , Comunicação Celular/imunologia , Glioblastoma/imunologia , Microambiente Tumoral/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/imunologia , Microglia/imunologia , Microglia/patologia , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia
16.
Biomolecules ; 11(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439829

RESUMO

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.


Assuntos
Antirreumáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Fator Inibidor de Leucemia/farmacologia , Mutação , Retina/efeitos dos fármacos , Retinite Pigmentosa/tratamento farmacológico , Rodopsina/genética , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Retina/imunologia , Retina/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/imunologia , Retinite Pigmentosa/patologia , Rodopsina/deficiência , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Transgenes , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445510

RESUMO

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b-GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.


Assuntos
Astrócitos/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Macrófagos/citologia , Microglia/citologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Comunicação Celular , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Ratos
18.
Nat Immunol ; 22(9): 1083-1092, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34429552

RESUMO

For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.


Assuntos
Encéfalo/imunologia , Imunidade/fisiologia , Microglia/imunologia , Doenças Neurodegenerativas/imunologia , Envelhecimento/imunologia , Barreira Hematoencefálica/imunologia , Células da Medula Óssea/imunologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/imunologia , Humanos , Subpopulações de Linfócitos/imunologia , Macrófagos/imunologia
19.
Cells ; 10(7)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34359956

RESUMO

Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS-affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNγ, IL1ß, and TNF, we observed, by RNA sequencing, marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell-cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.


Assuntos
Diferenciação Celular/fisiologia , Imunomodulação/imunologia , Células Precursoras de Oligodendrócitos/citologia , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Remielinização/fisiologia , Animais , Comunicação Celular/imunologia , Inflamação/imunologia , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
20.
Cells ; 10(8)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34440711

RESUMO

Microglia and astrocytes play an important role in the regulation of immune responses under various pathological conditions. To detect environmental cues associated with the transformation of reactive microglia (M1) and astrocytes (A1) into their polarization states (anti-inflammatory M2 and A2 phenotypes), we studied time-dependent gene expression in naive and injured spinal cord. The relationship between astrocytes and microglia and their polarization states were studied in a rat model after Th9 compression (40 g/15 min) in acute and subacute stages at the lesion site, and both cranially and caudally. The gene expression of microglia/macrophages and M1 microglia was strongly up-regulated at the lesion site and caudally one week after SCI, and attenuated after two weeks post-SCI. GFAP and S100B, and A1 astrocytes were profoundly expressed predominantly two weeks post-SCI at lesion site and cranially. Gene expression of anti-inflammatory M2a microglia (CD206, CHICHI, IL1rn, Arg-1), M2c microglia (TGF-ß, SOCS3, IL4R α) and A2 astrocytes (Tgm1, Ptx3, CD109) was greatly activated at the lesion site one week post-SCI. In addition, we observed positive correlation between neurological outcome and expression of M2a, M2c, and A2 markers. Our findings indicate that the first week post-injury is critical for modulation of reactive microglia/astrocytes into their neuroprotective phenotypes.


Assuntos
Astrócitos/metabolismo , Comportamento Animal , Mediadores da Inflamação/metabolismo , Locomoção , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/patologia , Proteínas do Tecido Nervoso/genética , Fenótipo , Ratos Wistar , Recuperação de Função Fisiológica , Transdução de Sinais , Medula Espinal/imunologia , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Fatores de Tempo
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