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1.
Nat Commun ; 12(1): 114, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414464

RESUMO

Emerging artificial enzymes with reprogrammed and augmented catalytic activity and substrate selectivity have long been pursued with sustained efforts. The majority of current candidates have rather poor catalytic activity compared with natural molecules. To tackle this limitation, we design artificial enzymes based on a structurally well-defined Au25 cluster, namely clusterzymes, which are endowed with intrinsic high catalytic activity and selectivity driven by single-atom substitutions with modulated bond lengths. Au24Cu1 and Au24Cd1 clusterzymes exhibit 137 and 160 times higher antioxidant capacities than natural trolox, respectively. Meanwhile, the clusterzymes demonstrate preferential enzyme-mimicking catalytic activities, with Au25, Au24Cu1 and Au24Cd1 displaying compelling selectivity in glutathione peroxidase-like (GPx-like), catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) activities, respectively. Au24Cu1 decreases peroxide in injured brain via catalytic reactions, while Au24Cd1 preferentially uses superoxide and nitrogenous signal molecules as substrates, and significantly decreases inflammation factors, indicative of an important role in mitigating neuroinflammation.


Assuntos
Enzimas/química , Inflamação , Neurônios/enzimologia , Compostos Organometálicos/química , Animais , Antioxidantes , Encéfalo/enzimologia , Catalase , Catálise , Linhagem Celular , Glutationa Peroxidase/química , Masculino , Metais/química , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neurônios/imunologia , Superóxido Dismutase/química , Superóxidos
2.
Neuron ; 107(5): 891-908.e8, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681824

RESUMO

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.


Assuntos
Proteína Huntingtina/imunologia , Doença de Huntington/imunologia , Imunidade Inata/imunologia , Neurônios/imunologia , RNA Mitocondrial/imunologia , Animais , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Mutação , Neurônios/patologia , Transcriptoma
3.
Toxicol Lett ; 331: 188-199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569805

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.


Assuntos
Astrócitos/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Exossomos/metabolismo , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Hipocampo/citologia , Humanos , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/metabolismo , Síndromes Neurotóxicas/imunologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Cultura Primária de Células , Sinucleinopatias/imunologia , Sinucleinopatias/metabolismo
4.
Cell Mol Life Sci ; 77(22): 4505-4522, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32424438

RESUMO

The enteric nervous system (ENS) is an extensive network comprising millions of neurons and glial cells contained within the wall of the gastrointestinal tract. The major functions of the ENS that have been most studied include the regulation of local gut motility, secretion, and blood flow. Other areas that have been gaining increased attention include its interaction with the immune system, with the gut microbiota and its involvement in the gut-brain axis, and neuro-epithelial interactions. Thus, the enteric circuitry plays a central role in intestinal homeostasis, and this becomes particularly evident when there are faults in its wiring such as in neurodevelopmental or neurodegenerative disorders. In this review, we first focus on the current knowledge on the cellular composition of enteric circuits. We then further discuss how enteric circuits detect and process external information, how these signals may be modulated by physiological and pathophysiological factors, and finally, how outputs are generated for integrated gut function.


Assuntos
Sistema Nervoso Entérico/fisiologia , Transdução de Sinais/fisiologia , Animais , Encéfalo/imunologia , Encéfalo/fisiologia , Sistema Nervoso Entérico/imunologia , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/fisiologia , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiologia , Neuroglia/imunologia , Neuroglia/fisiologia , Neurônios/imunologia , Neurônios/fisiologia , Transdução de Sinais/imunologia
5.
Mol Cells ; 43(5): 431-437, 2020 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-32392909

RESUMO

The hypothalamus is a crucial organ for the maintenance of appropriate body fat storage. Neurons in the hypothalamic arcuate nucleus (ARH) detect energy shortage or surplus via the circulating concentrations of metabolic hormones and nutrients, and then coordinate energy intake and expenditure to maintain energy homeostasis. Malfunction or loss of hypothalamic ARH neurons results in obesity. Accumulated evidence suggests that hypothalamic inflammation is a key pathological mechanism that links chronic overconsumption of a high-fat diet (HFD) with the development of obesity and related metabolic complications. Interestingly, overnutrition-induced hypothalamic inflammation occurs specifically in the ARH, where microglia initiate an inflammatory response by releasing proinflammatory cytokines and chemokines in response to excessive fatty acid flux. Upon more prolonged HFD consumption, astrocytes and perivascular macrophages become involved and sustain hypothalamic inflammation. ARH neurons are victims of hypothalamic inflammation, but they may actively participate in hypothalamic inflammation by sending quiescence or stress signals to surrounding glia. In this mini-review, we describe the current state of knowledge regarding the contributions of neurons and glia, and their interactions, to HFD-induced hypothalamic inflammation.


Assuntos
Tecido Adiposo/imunologia , Hipotálamo/imunologia , Inflamação/metabolismo , Macrófagos/imunologia , Microglia/imunologia , Neurônios/imunologia , Obesidade/imunologia , Animais , Citocinas/metabolismo , Dieta Hiperlipídica , Metabolismo Energético , Humanos , Imunidade Celular , Inflamação Neurogênica
6.
Med Sci (Paris) ; 36(5): 479-486, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32452370

RESUMO

Infection of the brain with various types of pathogens, and the resulting inflammatory response, is becoming increasingly important in our understanding of the etiology of Alzheimer's disease (AD). The fact that several genes identified as risk factors are actually involved in the modulation of the immune response, as well as the very diversity of the infectious agents identified as possible actors in the evolution of this disease, argue in favor of the neuro-inflammatory hypothesis, as does the demonstration that the protein Aß, one of the most important markers of AD, is an antimicrobial peptide. Among others, herpes viruses (mainly, but not only, HSV-1), which can establish latent infections in brain neurons, especially in the elder population, punctuated by episodes of reactivation following stress or immunosuppression, appear as very strong candidates to play an etiological role, if only as cofactors, of AD. Recent results show that, in human and rat neurons, infection with HSV-1 increases the formation of Aß along the amyloidogenic pathway, as well as the phosphorylation of Tau proteins, another essential marker of AD. The growing evidence that chronic infections and defense mechanisms, including inflammatory processes, are at the heart of AD, warrants reviewing antiviral drugs such as acyclovir, and possibly vaccination, as potential avenues for AD control.


Assuntos
Doença de Alzheimer/etiologia , Herpesviridae/fisiologia , Inflamação/complicações , Neurônios/imunologia , Neurônios/virologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Doença de Alzheimer/virologia , Animais , Antivirais/uso terapêutico , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Humanos , Inflamação/patologia , Inflamação/virologia , Neuroimunomodulação/fisiologia , Neurônios/patologia , Ratos , Fatores de Risco , Transdução de Sinais/fisiologia
7.
PLoS Biol ; 18(4): e3000665, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32275651

RESUMO

The correct subcellular distribution of proteins establishes the complex morphology and function of neurons. Fluorescence microscopy techniques are invaluable to investigate subcellular protein distribution, but they suffer from the limited ability to efficiently and reliably label endogenous proteins with fluorescent probes. We developed ORANGE: Open Resource for the Application of Neuronal Genome Editing, which mediates targeted genomic integration of epitope tags in rodent dissociated neuronal culture, in organotypic slices, and in vivo. ORANGE includes a knock-in library for in-depth investigation of endogenous protein distribution, viral vectors, and a detailed two-step cloning protocol to develop knock-ins for novel targets. Using ORANGE with (live-cell) superresolution microscopy, we revealed the dynamic nanoscale organization of endogenous neurotransmitter receptors and synaptic scaffolding proteins, as well as previously uncharacterized proteins. Finally, we developed a mechanism to create multiple knock-ins in neurons, mediating multiplex imaging of endogenous proteins. Thus, ORANGE enables quantification of expression, distribution, and dynamics for virtually any protein in neurons at nanoscale resolution.


Assuntos
Sistemas CRISPR-Cas , Epitopos/genética , Edição de Genes/métodos , Neurônios/imunologia , Proteínas/genética , Animais , Células Cultivadas , Dependovirus/genética , Feminino , Técnicas de Introdução de Genes , Genes Reporter , Vetores Genéticos , Genoma , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos Transgênicos , Microscopia de Fluorescência , Imagem Molecular/métodos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Proteínas/imunologia , Proteínas/metabolismo , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Análise Espaço-Temporal
8.
J Virol ; 94(12)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32269117

RESUMO

West Nile virus (WNV), a member of the Flavivirus genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to reemerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane glycoprotein (M) has been associated with Flavivirus-induced pathogenesis. Here, we identified a key amino acid residue at position 36 of the M protein whose mutation impacts WNV secretion and promotes viral attenuation. We also identified a compensatory site at position M-43 whose mutation stabilizes M-36 substitution both in vitro and in vivo Moreover, we found that introduction of the two mutations together confers a full attenuation phenotype and protection against wild-type WNV lethal challenge, eliciting potent neutralizing-antibody production in mice. Our study thus establishes the M protein as a new viral target for rational design of attenuated WNV strains.IMPORTANCE West Nile virus (WNV) is a worldwide (re)emerging mosquito-transmitted Flavivirus causing fatal neurological diseases in humans. However, no human vaccine has been yet approved. One of the most effective live-attenuated vaccines was empirically obtained by serial passaging of wild-type yellow fever Flavivirus However, such an approach is not acceptable nowadays, and the development of a rationally designed vaccine is necessary. Generating molecular infectious clones and mutating specific residues known to be involved in Flavivirus virulence constitute a powerful tool to promote viral attenuation. WNV membrane glycoprotein is thought to carry such essential determinants. Here, we identified two residues of this protein whose substitutions are key to the full and stable attenuation of WNV in vivo, most likely through inhibition of secretion and possible alteration of morphology. Applied to other flaviviruses, this approach should help in designing new vaccines against these viruses, which are an increasing threat to global human health.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Glicoproteínas de Membrana/genética , Mutação , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Expressão Gênica , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neurônios/imunologia , Neurônios/virologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Análise de Sobrevida , Células Vero , Proteínas Virais , Febre do Nilo Ocidental/imunologia , Febre do Nilo Ocidental/mortalidade , Febre do Nilo Ocidental/patologia , Vírus do Nilo Ocidental/crescimento & desenvolvimento , Vírus do Nilo Ocidental/imunologia
9.
Proc Natl Acad Sci U S A ; 117(12): 6844-6854, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32144141

RESUMO

Chronic inflammation during Alzheimer's disease (AD) is most often attributed to sustained microglial activation in response to amyloid-ß (Aß) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be at play during the earliest AD-related immune response. We propose that this plaque-independent inflammatory reaction originates from neurons burdened with increasing levels of soluble and oligomeric Aß, which are known to be the most toxic amyloid species within the brain. Laser microdissected neurons extracted from preplaque amyloid precursor protein (APP) transgenic rats were found to produce a variety of potent immune factors, both at the transcript and protein levels. Neuron-derived cytokines correlated with the extent of microglial activation and mobilization, even in the absence of extracellular plaques and cell death. Importantly, we identified an inflammatory profile unique to Aß-burdened neurons, since neighboring glial cells did not express similar molecules. Moreover, we demonstrate within disease-vulnerable regions of the human brain that a neuron-specific inflammatory response may precede insoluble Aß plaque and tau tangle formation. Thus, we reveal the Aß-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of Aß as a significant immunological component in the AD pathogenesis.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/patologia , Inflamação/patologia , Neurônios/imunologia , Placa Amiloide/patologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Amiloidose , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/patologia , Placa Amiloide/imunologia , Placa Amiloide/metabolismo , Ratos , Ratos Transgênicos
10.
Nat Commun ; 11(1): 1403, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179753

RESUMO

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.


Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/psicologia , Receptores de N-Metil-D-Aspartato/imunologia , Memória Espacial , Animais , Morte Celular , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Neurônios/imunologia , Receptores de N-Metil-D-Aspartato/genética
11.
Brain ; 143(3): 960-975, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203581

RESUMO

We performed post-mortem studies on two patients with advanced Parkinson's disease 8 and10 years following AAV2-neurturin (CERE120) gene therapy, the longest post-mortem trophic factor gene therapy cases reported to date. CERE120 was delivered to the putamen bilaterally in one case (10 years post-surgery), and to the putamen plus the substantia nigra bilaterally in the second (8 years post-surgery). In both patients there was persistent, albeit limited, neurturin expression in the putamen covering ∼3-12% of the putamen. In the putamen, dense staining of tyrosine hydroxylase-positive fibres was observed in areas that contained detectable neurturin expression. In the substantia nigra, neurturin expression was detected in 9.8-18.95% and 22.02-39% of remaining melanin-containing neurons in the patient with putamenal and combined putamenal and nigral gene delivery, respectively. Melanized neurons displayed intense tyrosine hydroxylase and RET proto-oncogene expression in nigral neurons in the patient where CERE120 was directly delivered to the nigra. There was no difference in the degree of Lewy pathology in comparison to untreated control patients with Parkinson's disease, and α-synuclein aggregates were detected in neurons that also stained for neurturin, RET, and tyrosine hydroxylase. These changes were not associated with antiparkinsonian benefits likely due to the limited neurturin expression. This study provides the longest term evidence of persistent transgene expression following gene delivery to the CNS and the first human results when targeting both the terminal fields in the putamen as well as the originating nigral neurons.


Assuntos
Terapia Genética , Neurturina/biossíntese , Doença de Parkinson/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Corpos de Lewy/metabolismo , Melaninas/imunologia , Pessoa de Meia-Idade , Neurônios/imunologia , Neurturina/administração & dosagem , Doença de Parkinson/imunologia , Proteínas Proto-Oncogênicas c-ret/biossíntese , Putamen/imunologia , Putamen/metabolismo , Substância Negra/imunologia , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/imunologia , alfa-Sinucleína/metabolismo
12.
Proc Natl Acad Sci U S A ; 117(12): 6708-6716, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32161123

RESUMO

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group A Streptococcus (GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood-brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.


Assuntos
Encéfalo/patologia , Modelos Animais de Doenças , Encefalite/etiologia , Encefalomielite Autoimune Experimental/etiologia , Doença de Hashimoto/etiologia , Transtornos do Olfato/etiologia , Infecções Estreptocócicas/complicações , Células Th17/imunologia , Animais , Autoanticorpos/imunologia , Gânglios da Base/imunologia , Gânglios da Base/patologia , Barreira Hematoencefálica , Encéfalo/imunologia , Encefalite/metabolismo , Encefalite/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Doença de Hashimoto/metabolismo , Doença de Hashimoto/patologia , Camundongos , Microglia/imunologia , Microglia/patologia , Neurônios/imunologia , Neurônios/patologia , Transtornos do Olfato/metabolismo , Transtornos do Olfato/patologia , Percepção Olfatória , Streptococcus pyogenes/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/patologia
13.
Immunity ; 52(3): 464-474, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187517

RESUMO

The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease.


Assuntos
Sistema Imunitário/imunologia , Sistema Nervoso/imunologia , Neuroimunomodulação/imunologia , Neurônios/imunologia , Animais , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Imunidade Inata/imunologia , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Inflamação Neurogênica/imunologia , Inflamação Neurogênica/metabolismo , Neurônios/metabolismo , Neuropeptídeos/imunologia , Neuropeptídeos/metabolismo , Transdução de Sinais/imunologia
14.
Nat Rev Immunol ; 20(5): 308-320, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32015472

RESUMO

Memories of previous immune events enable barrier tissues to rapidly recall distinct environmental exposures. To effectively inform future responses, these past experiences can be stored in cell types that are long-term residents or essential constituents of tissues. There is an emerging understanding that, in addition to antigen-specific immune cells, diverse haematopoietic, stromal, parenchymal and neuronal cell types can store inflammatory memory. Here, we explore the impact of previous immune activity on various cell lineages with the goal of presenting a unified view of inflammatory memory to environmental exposures (such as allergens, antigens, noxious agents and microorganisms) at barrier tissues. We propose that inflammatory memory is distributed across diverse cell types and stored through shifts in cell states, and we provide a framework to guide future experiments. This distribution and storage may promote adaptation or maladaptation in homeostatic, maintenance and disease settings - especially if the distribution of memory favours cellular cooperation during storage or recall.


Assuntos
Linfócitos B/imunologia , Células Epiteliais/imunologia , Epitélio/imunologia , Memória Imunológica/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Linhagem da Célula , Células Dendríticas/imunologia , Humanos , Imunidade Inata , Neurônios/imunologia , Plasmócitos/imunologia , Células Estromais/imunologia
15.
Nanotoxicology ; 14(5): 595-611, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32091294

RESUMO

Carbon black nanoparticles (CBNPs) can enter the central nervous system through blood circulation and olfactory nerves, affecting brain development or increasing neurological disease susceptibility. However, whether CBNPs exposure affects seizure is unclear. Herein, mice were exposed to two different doses of CBNPs (21 and 103 µg/animal) based on previous studies and the maximum exposure limitation (4 mg/m3) in occupational workplaces set by the Chinese government. In the pentylenetetrazol (PTZ) and kainic acid (KA) seizure models, high-dose CBNPs exposure increased seizure susceptibility in both models and increased spontaneous recurrent seizure (SRS) frequency in the KA model. In vivo local field potential (LFP) recording in KA model mice revealed that both low-dose and high-dose CBNPs exposure increased seizure-like event (SLE) frequency in the SRS interval but shortened SLE duration. Intriguingly, H&E staining and Nissl staining on brain tissue revealed that CBNPs exposure did not cause significant brain tissue morphology or neuronal damage. Detection of inflammatory factors, such as TNF-α, TGF-ß1, IL-1ß, and IL-6, in brain tissue showed that only high dose of CBNPs exposure increased the expression of cortical TGF-ß1. By using the primary cultured neurons, we observed that CBNPs exposure not only significantly decreased the expression of the neuronal marker MAP2 but also enhanced the levels of action potential frequency in the neurons. In general, CBNPs exposure can affect abnormal epileptic discharges during the seizure interval and enhance susceptibility to frequent seizures. Our findings suggest that minimizing CBNPs exposure may be a potential way to prevent or ease seizure.


Assuntos
Encéfalo/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Nanopartículas/toxicidade , Neurônios/efeitos dos fármacos , Convulsões/induzido quimicamente , Fuligem/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Encéfalo/imunologia , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Exposição por Inalação/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neurônios/imunologia , Neurônios/patologia , Tamanho da Partícula , Técnicas de Patch-Clamp , Recidiva , Convulsões/patologia , Fuligem/química , Propriedades de Superfície
16.
PLoS One ; 15(2): e0229362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078657

RESUMO

In the mature rodent brain, Sonic Hedgehog (Shh) signaling regulates stem and progenitor cell maintenance, neuronal and glial circuitry and brain repair. However, the sources and distribution of Shh mediating these effects are still poorly characterized. Here, we report in the adult mouse brain, a broad expression pattern of Shh recognized by the specific monoclonal C9C5 antibody in a subset (11-12%) of CC1+ mature oligodendrocytes that do not express carbonic anhydrase II. These cells express also Olig2 and Sox10, two oligodendrocyte lineage-specific markers, but not PDGFRα, a marker of oligodendrocyte progenitors. In agreement with oligodendroglial cells being a source of Shh in the adult mouse brain, we identify Shh transcripts by single molecule fluorescent in situ hybridization in a subset of cells expressing Olig2 and Sox10 mRNAs. These findings also reveal that Shh expression is more extensive than originally reported. The Shh-C9C5-associated signal labels the oligodendroglial cell body and decorates by intense puncta the processes. C9C5+ cells are distributed in a grid-like manner. They constitute small units that could deliver locally Shh to its receptor Patched expressed in GFAP+ and S100ß+ astrocytes, and in HuC/D+ neurons as shown in PtcLacZ/+ reporter mice. Postnatally, C9C5 immunoreactivity overlaps the myelination peak that occurs between P10 and P20 and is down regulated during ageing. Thus, our data suggest that C9C5+CC1+ oligodendroglial cells are a source of Shh in the mouse postnatal brain.


Assuntos
Anticorpos Monoclonais/imunologia , Encéfalo/metabolismo , Proteínas Hedgehog/imunologia , Proteínas Hedgehog/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Animais , Encéfalo/imunologia , Células Cultivadas , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Oligodendroglia/imunologia , Receptores Patched/imunologia , Receptores Patched/metabolismo
17.
J Neuroimmunol ; 340: 577149, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31951874

RESUMO

Since approximately 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS) subsequently develop small-cell lung cancer (SCLC), it is important to be able to predict cancer occurrence in these patients at neurological presentation. We aimed to determine whether circulating biomarkers were effective and objective predictors of cancer development in LEMS. We found that the presence of either SOX2, N-type voltage gated calcium channel or GABAb antibodies at LEMS diagnosis was highly sensitive (84%) and specific (87%) for the detection of SCLC. Screening for SOX2 and neuronal antibodies is a useful adjunct to clinical predictive scoring tools in predicting SCLC in LEMS.


Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Síndrome Miastênica de Lambert-Eaton/complicações , Neoplasias Pulmonares/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Feminino , Humanos , Síndrome Miastênica de Lambert-Eaton/imunologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Neurônios/imunologia , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/diagnóstico
18.
Cell ; 180(1): 50-63.e12, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31923399

RESUMO

Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.


Assuntos
Imunidade nas Mucosas/imunologia , Interleucina-18/imunologia , Mucosa Intestinal/imunologia , Animais , Citocinas/imunologia , Sistema Nervoso Entérico/imunologia , Sistema Nervoso Entérico/metabolismo , Células Epiteliais/imunologia , Feminino , Células Caliciformes/imunologia , Interleucina-18/biossíntese , Mucosa Intestinal/metabolismo , Intestino Delgado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Ratos , Ratos Sprague-Dawley , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Transdução de Sinais/imunologia
19.
Nat Rev Neurosci ; 21(2): 93-102, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31913356

RESUMO

A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Homeostase , Doenças Neurodegenerativas/fisiopatologia , Envelhecimento/imunologia , Animais , Encéfalo/imunologia , Células Endoteliais/imunologia , Células Endoteliais/fisiologia , Exercício Físico/fisiologia , Humanos , Microbiota/imunologia , Microbiota/fisiologia , Doenças Neurodegenerativas/imunologia , Neuroglia/imunologia , Neuroglia/fisiologia , Neurônios/imunologia , Neurônios/fisiologia
20.
Curr Top Behav Neurosci ; 44: 85-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31292938

RESUMO

Research into antibody-mediated disease, in response to immune dysfunction or to tumour development, has rapidly expanded in recent years. Antibodies binding to neuroreceptors can cause psychiatric features, including psychosis, in a minority of patients as well as neurological features. The responsiveness of some of these cases to immunotherapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic diseases. The purpose of this chapter is to review autoantibodies that are most likely to be relevant for patients with psychotic symptoms. Herein, we describe receptor structure and mechanism of action, clinical and psychiatric features for the growing number of neuronal surface antibodies, including those to the N-methyl-D-aspartate (NMDA) receptor. The identification of a subgroup of patients with psychiatric features having antibody-mediated disease highlights the importance of considering the diagnosis, particularly in those patients presenting with a first episode of psychosis.


Assuntos
Autoanticorpos , Transtornos Psicóticos , Humanos , Neurônios/imunologia , Transtornos Psicóticos/imunologia , Receptores de N-Metil-D-Aspartato/imunologia
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