RESUMO
OBJECTIVE: To describe the clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy in children. METHOD: Data from 11 pediatric patients with autoimmune GFAP astrocytopathy were retrospectively analyzed. RESULTS: All of the patients showed encephalitis and meningoencephalitis or meningoencephalomyelitis with or without myelitis. 45.4% of the patients had fever, 27.3% headaches, 18.2% dizziness, 18.2% drowsiness, and 18.2% mental disorders. Cerebrospinal fluid (CSF) was detected in all patients. The white blood cell counts (WBC) (90.9%), lactic dehydrogenase levels (72.7%), protein level (36.4%), and adenosine deaminase activity (ADA) level (27.3%) were elevated, and the CSF glucose levels (72.7%) were slightly reduced. Nine patients (90%) were found to have brain abnormalities, of which five (50.0%) patients had abnormal symmetrical laminar patterns or line patterns hyperintensity lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in the basal ganglia, hypothalamus, subcortical white matter and periventricular white matter. The linear radial enhancement pattern of the cerebral white matter was only seen in two patients, with the most common being abnormal enhancement of leptomeninges (50%). Five patients had longitudinally extensive spinal cord lesions. CONCLUSION: The findings of pediatric patients with autoimmune GFAP astrocytopathy are different from previous reports.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Proteína Glial Fibrilar Ácida/imunologia , Gliose/imunologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Pré-Escolar , Feminino , Seguimentos , Gliose/diagnóstico , Gliose/metabolismo , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
Prenatal inflammation negatively affects placental function, subsequently altering fetal development. Pathogen-associated molecular patterns (PAMPs) are used to mimics infections in preclinical models but rarely detected during pregnancy. Our group previously developed an animal model of prenatal exposure to uric acid (endogenous mediator), leading to growth restriction alongside IL-1-driven placental inflammation (Brien et al. in J Immunol 198(1):443-451, 2017). Unlike PAMPs, the postnatal impact of prenatal non-pathogenic inflammation is still poorly understood. Therefore, we investigated the effects of prenatal uric acid exposure on postnatal neurodevelopment and the therapeutic potential of the IL-1 receptor antagonist; IL-1Ra. Uric acid induced growth restriction and placental inflammation, which IL-1Ra protected against. Postnatal evaluation of both structural and functional aspects of the brain revealed developmental changes. Both astrogliosis and microgliosis were observed in the hippocampus and white matter at postnatal day (PND)7 with IL-1Ra being protective. Decreased myelin density was observed at PND21, and reduced amount of neuronal precursor cells was observed in the Dentate Gyrus at PND35. Functionally, motor impairments were observed as evaluated with the increased time to fully turn upward (180 degrees) on the inclined plane and the pups were weaker on the grip strength test. Prenatal exposure to sterile inflammation, mimicking most clinical situation, induced growth restriction with negative impact on neurodevelopment. Targeted anti-inflammatory intervention prenatally could offer a strategy to protect brain development during pregnancy.
Assuntos
Retardo do Crescimento Fetal/tratamento farmacológico , Gliose/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Placenta/efeitos dos fármacos , Ácido Úrico/efeitos adversos , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/imunologia , Gliose/induzido quimicamente , Gliose/imunologia , Inflamação/induzido quimicamente , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Placenta/imunologia , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
In recent years, much attention has been paid to the study of the therapeutic effect of the microelement selenium, its compounds, especially selenium nanoparticles, with a large number of works devoted to their anticancer effects. Studies proving the neuroprotective properties of selenium nanoparticles in various neurodegenerative diseases began to appear only in the last 5 years. Nevertheless, the mechanisms of the neuroprotective action of selenium nanoparticles under conditions of ischemia and reoxygenation remain unexplored, especially for intracellular Ca2+ signaling and neuroglial interactions. This work is devoted to the study of the cytoprotective mechanisms of selenium nanoparticles in the neuroglial networks of the cerebral cortex under conditions of ischemia/reoxygenation. It was shown for the first time that selenium nanoparticles dose-dependently induce the generation of Ca2+ signals selectively in astrocytes obtained from different parts of the brain. The generation of these Ca2+ signals by astrocytes occurs through the release of Ca2+ ions from the endoplasmic reticulum through the IP3 receptor upon activation of the phosphoinositide signaling pathway. An increase in the concentration of cytosolic Ca2+ in astrocytes leads to the opening of connexin Cx43 hemichannels and the release of ATP and lactate into the extracellular medium, which trigger paracrine activation of the astrocytic network through purinergic receptors. Incubation of cerebral cortex cells with selenium nanoparticles suppresses ischemia-induced increase in cytosolic Ca2+ and necrotic cell death. Activation of A2 reactive astrocytes exclusively after ischemia/reoxygenation, a decrease in the expression level of a number of proapoptotic and proinflammatory genes, an increase in lactate release by astrocytes, and suppression of the hyperexcitation of neuronal networks formed the basis of the cytoprotective effect of selenium nanoparticles in our studies.
Assuntos
Astrócitos/citologia , Cálcio/metabolismo , Gliose/tratamento farmacológico , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Selênio/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/metabolismo , Sinalização do Cálcio , Gliose/imunologia , Gliose/metabolismo , Gliose/patologia , Nanopartículas/química , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Ratos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Selênio/químicaRESUMO
The pathological role of reactive gliosis in CNS repair remains controversial. In this study, using murine ischemic and hemorrhagic stroke models, we demonstrated that microglia/macrophages and astrocytes are differentially involved in engulfing synapses in the reactive gliosis region. By specifically deleting MEGF10 and MERTK phagocytic receptors, we determined that inhibiting phagocytosis of microglia/macrophages or astrocytes in ischemic stroke improved neurobehavioral outcomes and attenuated brain damage. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed that phagocytosis related biological processes and pathways were downregulated in astrocytes of the hemorrhagic brain compared to the ischemic brain. Together, these findings suggest that reactive microgliosis and astrogliosis play individual roles in mediating synapse engulfment in pathologically distinct murine stroke models and preventing this process could rescue synapse loss.
Assuntos
Encéfalo/patologia , Gliose/imunologia , Infarto da Artéria Cerebral Média/complicações , Sinapses/patologia , Animais , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Gliose/patologia , Humanos , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Fagocitose/genética , Fagocitose/imunologia , RNA-Seq , Análise de Célula Única , Sinapses/imunologia , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismoRESUMO
A disproportionate increase in activated nuclear factor-kappa B (NF-κB) has been shown to drive the Aß deposition, neuroinflammation and neurodegeneration in Alzheimer's disease (AD). Hence, selective targeting of activated p65 represents an attractive therapeutic approach for AD. Glucocorticoid induced leucine zipper (GILZ) is a NF-κB interactant that binds and sequesters the activated p65 in the cytoplasm. The p65 binding domain of GILZ adopts a polyproline type II helical conformation, a motif that acts as an adaptable glove in the interface with the binding partner and constitutes an excellent template for drug design. Previously, peptide analogs of the p65 binding domain of GILZ, referred to as GA have been shown to suppress pathology in the lipopolysaccharide induced model of neuroinflammation. In this study, we investigated the CNS delivery of labeled GA administered intraperitoneally in adult mice for a period of upto 24 h. Further, we evaluated the suppressive potential of GA in 5xFAD mice, an aggressive model with five genetic mutations closely associated with human AD. Groups of 5xFAD mice administered GA or control peptide intraperitoneally on alternate days for six weeks were evaluated for Aß deposition, microglia, inflammation and innate immune responses by immunohistochemistry and real time polymerase reaction. GA was observed in proximity with NeuN positive neurons suggesting that the compound crossed the blood brain barrier to reach the brain parenchyma. Further, GA treatment decreased Aß load, reduced Iba1 + microglia and glial fibrillary acidic protein (GFAP)+ astrocytes, inhibited inflammatory cytokines and suppressed toll like receptor (TLR-2, TLR-4) expressions in 5xFAD mice.
Assuntos
Doença de Alzheimer/prevenção & controle , Gliose/prevenção & controle , Imunidade Inata/efeitos dos fármacos , NF-kappa B/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Fatores de Transcrição/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Animais , Feminino , Gliose/genética , Gliose/imunologia , Imunidade Inata/fisiologia , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , NF-kappa B/genética , NF-kappa B/uso terapêutico , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Fatores de Transcrição/uso terapêutico , eIF-2 Quinase/genética , eIF-2 Quinase/imunologiaRESUMO
Unraveling the pathology of stroke is a prerequisite for designing therapeutic strategies. It was reported that myelin injury exceeded axonal loss in the peri-infarct region of rodent white matter stroke. An in-depth investigation of the post-stroke white matter damage in higher-order species might innovate stroke intervention. In this study, adult male cynomolgus monkeys received surgical middle cerebral artery occlusion (MCAO), and serial magnetic resonance scans to non-invasively assess brain damage. Spontaneous movements were recorded to evaluate post-stroke behavior. The axon and myelin loss, as well as immune cell infiltration were examined using immunohistochemistry. Magnetic resonance imaging revealed cerebral infarcts and white matter injury after MCAO in monkeys, which were confirmed by neurological deficits. Immunostaining of white matter fibers showed substantial demyelination whilst retention of axons in the infarcts 8 days post MCAO, while a progressive loss of myelin and axons was observed after one month. Gliosis, microglia activation, and leukocyte infiltration were identified in the lesions. These results demonstrate that demyelination predates axonal injury in non-human primate ischemic stroke, which provides a time window for stroke intervention focusing on prevention of progressive axonal loss through myelin regeneration.
Assuntos
Axônios/patologia , Isquemia Encefálica/patologia , Doenças Desmielinizantes/patologia , AVC Isquêmico/patologia , Substância Branca/patologia , Animais , Axônios/química , Axônios/imunologia , Isquemia Encefálica/imunologia , Doenças Desmielinizantes/imunologia , Gliose/imunologia , Gliose/patologia , AVC Isquêmico/imunologia , Macaca fascicularis , Masculino , Substância Branca/química , Substância Branca/imunologiaRESUMO
Previous studies demonstrated that retinal damage correlates with a massive remodeling of extracellular matrix (ECM) molecules and reactive gliosis. However, the functional significance of the ECM in retinal neurodegeneration is still unknown. In the present study, we used an intraocular pressure (IOP) independent experimental autoimmune glaucoma (EAG) mouse model to examine the role of the ECM glycoprotein tenascin-C (Tnc). Wild type (WT ONA) and Tnc knockout (KO ONA) mice were immunized with an optic nerve antigen (ONA) homogenate and control groups (CO) obtained sodium chloride (WT CO, KO CO). IOP was measured weekly and electroretinographies were recorded at the end of the study. Ten weeks after immunization, we analyzed retinal ganglion cells (RGCs), glial cells, and the expression of different cytokines in retina and optic nerve tissue in all four groups. IOP and retinal function were comparable in all groups. Although RGC loss was less severe in KO ONA, WT as well as KO mice displayed a significant cell loss after immunization. Compared to KO ONA, less ßIII-tubulin+ axons, and downregulated oligodendrocyte markers were noted in WT ONA optic nerves. In retina and optic nerve, we found an enhanced GFAP+ staining area of astrocytes in immunized WT. A significantly higher number of retinal Iba1+ microglia was found in WT ONA, while a lower number of Iba1+ cells was observed in KO ONA. Furthermore, an increased expression of the glial markers Gfap, Iba1, Nos2, and Cd68 was detected in retinal and optic nerve tissue of WT ONA, whereas comparable levels were observed in KO ONA. In addition, pro-inflammatory Tnfa expression was upregulated in WT ONA, but downregulated in KO ONA. Vice versa, a significantly increased anti-inflammatory Tgfb1 expression was measured in KO ONA animals. We conclude that Tnc plays an important role in glial and inflammatory response during retinal neurodegeneration. Our results provide evidence that Tnc is involved in glaucomatous damage by regulating retinal glial activation and cytokine release. Thus, this transgenic EAG mouse model for the first time offers the possibility to investigate IOP-independent glaucomatous damage in direct relation to ECM remodeling.
Assuntos
Doenças Autoimunes/imunologia , Glaucoma/imunologia , Tenascina/imunologia , Animais , Antígenos/administração & dosagem , Citocinas/imunologia , Modelos Animais de Doenças , Matriz Extracelular , Feminino , Gliose/imunologia , Imunização , Masculino , Camundongos Knockout , Células Ganglionares da Retina/imunologia , Tenascina/genéticaRESUMO
Antibodies have been explored extensively as a potential therapeutic for Alzheimer's disease, where amyloid-ß (Aß) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aß, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT-/-) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT-/- mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.
Assuntos
Autoanticorpos , Linfócitos B/imunologia , Gliose/genética , Gliose/imunologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/imunologia , Proteínas tau/genética , Proteínas tau/imunologia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos Transgênicos , Mutação , Proteínas tau/metabolismoRESUMO
The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.
Assuntos
Aracnoidite/imunologia , Gliose/imunologia , Traumatismos da Medula Espinal/complicações , Medula Espinal/patologia , Animais , Anti-Inflamatórios , Aracnoidite/diagnóstico , Aracnoidite/patologia , Astrócitos/imunologia , Astrócitos/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Gliose/diagnóstico , Gliose/patologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Masculino , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Ratos , Índice de Gravidade de Doença , Medula Espinal/citologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/imunologia , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Fatores de TempoRESUMO
Neuro-inflammation is widely regarded as the inflammation occurred in the central nervous system (CNS) tissue, which authentically involved in the pathogenesis such as depression although the underlying mechanism remains to be elucidated. Malva sylvestris (MS), a plant widely used in traditional medicine to mitigate urological, respiratory and oral diseases, exhibits excellent anti-oxidative and anti-inflammatory properties. In the present study, we first used LPS-induced depression-like mice to evaluate the neuro-protective effect of MS extract. We found that, after 7â¯days' administration of MS extract, the cognitive impairment of LPS-induced depression-like mice was efficiently alleviated, evaluated by behavioral test including the Open field, Morris water maze (MWM), Elevated plus-maze (EPM) and Rota-rod test. Furthermore, we found that MS extract also inhibited the LPS-induced neuron apoptosis and astrogliosis both in the cortex and the CA1 region of hippocampus. Finally, our findings showed that the extract of MS relieved inflammatory stress induced by LPS injury, indicated by the down-regulation of IL-1ß/6 and TNF-α, and up-regulation of IL-4 level both in vitro and in vivo. Collectively, MS extract exhibits neuro-protective activity in vivo, and therefore, it may be widely used for food to relieve the symptoms of neuro-inflammation associated disorders such as depression.
Assuntos
Anti-Inflamatórios/uso terapêutico , Astrócitos/efeitos dos fármacos , Depressão/tratamento farmacológico , Gliose/tratamento farmacológico , Malva , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Astrócitos/imunologia , Astrócitos/metabolismo , Linhagem Celular , Depressão/induzido quimicamente , Depressão/imunologia , Depressão/metabolismo , Gliose/imunologia , Gliose/metabolismo , Lipopolissacarídeos/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Componentes Aéreos da Planta , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Distribuição AleatóriaRESUMO
BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. T cells were shown to infiltrate the brain during the first days after injury and to exacerbate tissue damage. The objective of this study was to investigate the hitherto unresolved role of immunosuppressive, regulatory T cells (Tregs) in experimental TBI. METHODS: "Depletion of regulatory T cell" (DEREG) and wild type (WT) C57Bl/6 mice, treated with diphtheria toxin (DTx) to deplete Tregs or to serve as control, were subjected to the controlled cortical impact (CCI) model of TBI. Neurological and motor deficits were examined until 5 days post-injury (dpi). At the 5 dpi endpoint, (immuno-) histological, protein, and gene expression analyses were carried out to evaluate the consequences of Tregs depletion. Comparison of parametric or non-parametric data between two groups was done using Student's t test or the Mann-Whitney U test. For multiple comparisons, p values were calculated by one-way or two-way ANOVA followed by specific post hoc tests. RESULTS: The overall neurological outcome at 5 dpi was not different between DEREG and WT mice but more severe motor deficits occurred transiently at 1 dpi in DEREG mice. DEREG and WT mice did not differ in the extent of brain damage, blood-brain barrier (BBB) disruption, or neuronal excitotoxicity, as examined by lesion volumetry, immunoglobulin G (IgG) extravasation, or calpain-generated αII-spectrin breakdown products (SBDPs), respectively. In contrast, increased protein levels of glial fibrillary acidic protein (GFAP) and GFAP+ astrocytes in the ipsilesional brain tissue indicated exaggerated reactive astrogliosis in DEREG mice. T cell counts following anti-CD3 immunohistochemistry and gene expression analyses of Cd247 (CD3 subunit zeta) and Cd8a (CD8a) further indicated an increased number of T cells infiltrating the brain injury sites of DEREG mice compared to WT. These changes coincided with increased gene expression of pro-inflammatory interferon-γ (Ifng) in DEREG mice compared to WT in the injured brain. CONCLUSIONS: The results show that the depletion of Tregs attenuates T cell brain infiltration, reactive astrogliosis, interferon-γ gene expression, and transiently motor deficits in murine acute traumatic brain injury.
Assuntos
Astrócitos/patologia , Lesões Encefálicas Traumáticas/patologia , Encéfalo/patologia , Gliose/patologia , Interferon gama/genética , Depleção Linfocítica , Linfócitos T Reguladores/patologia , Animais , Astrócitos/imunologia , Encéfalo/imunologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/imunologia , Modelos Animais de Doenças , Gliose/genética , Gliose/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Linfócitos T Reguladores/imunologiaRESUMO
Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-ß, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.
Assuntos
Doenças Neurodegenerativas/imunologia , Transdução de Sinais/imunologia , Envelhecimento/imunologia , Animais , Ativação do Complemento , Progressão da Doença , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gliose/imunologia , Gliose/patologia , Humanos , Imunidade Inata , Inflamação/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Modelos Imunológicos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Agregação Patológica de Proteínas/imunologia , Receptores Imunológicos/imunologia , Fator de Crescimento Transformador beta/imunologiaRESUMO
There is a large body of evidence suggesting that parasites could be a major preventable risk factor for epilepsy in low- and middle-income countries. We review potentially important substrates for epileptogenesis in parasitic diseases. Taenia solium is the most widely known parasite associated with epilepsy, and the risk seems determined mainly by the extent of cortical involvement and the evolution of the primary cortical lesion to gliosis or to a calcified granuloma. For most parasites, however, epileptogenesis is more complex, and other favorable host genetic factors and parasite-specific characteristics may be critical. In situations where cortical involvement by the parasite is either absent or minimal, parasite-induced epileptogenesis through an autoimmune process seems plausible. Further research to identify important markers of epileptogenesis in parasitic diseases will have huge implications for the development of trials to halt or delay onset of epilepsy.
Assuntos
Epilepsia/epidemiologia , Epilepsia/parasitologia , Doenças Parasitárias/epidemiologia , Animais , Epilepsia/imunologia , Gliose/imunologia , Gliose/parasitologia , Gliose/patologia , Humanos , Parasitos/imunologia , Parasitos/isolamento & purificação , Doenças Parasitárias/imunologia , Taenia solium/imunologia , Taenia solium/isolamento & purificação , Teníase/epidemiologia , Teníase/imunologiaRESUMO
Mutations in Cu/Zn superoxide dismutase (SOD1) are the cause of ~20% of cases of familial ALS (FALS), which comprise ~10% of the overall total number of cases of ALS. Mutant (mt) SOD1 is thought to cause FALS through a gain and not loss in function, perhaps as a result of the mutant protein's misfolding and aggregation. Previously we used a phage display library to raise single chain variable fragment antibodies (scFvs) against SOD1, which were found to decrease aggregation of mtSOD1 and toxicity in vitro. In the present study, we show that two scFvs directed against SOD1 ameliorate disease in G93A mtSOD1 transgenic mice and also decrease motor neuron loss, microgliosis, astrocytosis, as well as SOD1 burden and aggregation. The results suggest that the use of antibodies or antibody mimetics directed against SOD1 may be a useful therapeutic direction in mtSOD1-induced FALS. Since studies suggest that wild type SOD1 may be misfolded similar to that seen with mtSOD1, this therapeutic direction may be effective in sporadic as well as FALS.
Assuntos
Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/patologia , Anticorpos de Cadeia Única/administração & dosagem , Superóxido Dismutase/imunologia , Animais , Modelos Animais de Doenças , Feminino , Gliose/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/imunologia , Agregação Patológica de Proteínas/imunologia , Medula Espinal/imunologia , Medula Espinal/patologia , Superóxido Dismutase/genéticaRESUMO
The eye is an immuno-privileged organ. However, certain diseases such as uveitis are intrinsically linked to inflammation. In several retinal degenerative diseases, there is a unique damage at the onset of the disease, but evidence suggests that chronic and low-grade inflammatory processes play an important role in their progression. Studies have identified similar signaling pathways and changes in resident immune cells within the retina among these diseases. Herein, we will discuss some of these studies and propose how understanding this inflammatory response could aid in the development of therapies.
Assuntos
Retinopatia Diabética/imunologia , Degeneração Macular/imunologia , Retinose Pigmentar/imunologia , Animais , Antígenos de Neoplasias/fisiologia , Citocinas/fisiologia , Retinopatia Diabética/patologia , Células Ependimogliais/imunologia , Células Ependimogliais/patologia , Gliose/imunologia , Gliose/patologia , Humanos , Inflamassomos/fisiologia , Inflamação , Degeneração Macular/patologia , Camundongos , Microglia/imunologia , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Receptor para Produtos Finais de Glicação Avançada/deficiência , Retina/imunologia , Retina/patologia , Drusas Retinianas/imunologia , Drusas Retinianas/patologia , Retinose Pigmentar/patologiaRESUMO
Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?
Assuntos
Retinopatia Diabética , Células Ependimogliais/fisiologia , Gliose , Inflamação , Fatores de Crescimento Neural/fisiologia , Estresse Oxidativo/fisiologia , Animais , Retinopatia Diabética/imunologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/fisiopatologia , Células Ependimogliais/imunologia , Células Ependimogliais/metabolismo , Gliose/imunologia , Gliose/metabolismo , Gliose/fisiopatologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Fatores de Crescimento Neural/imunologia , Fatores de Crescimento Neural/metabolismo , Estresse Oxidativo/imunologiaRESUMO
Astrocytes participate in both physiological and pathophysiological responses to metabolic and nutrient signals. Although most studies have focused on the astrocytic response to weight gain due to high-fat/high-carbohydrate intake, surplus intake of a balanced diet also induces excess weight gain. We have accessed the effects of neonatal overnutrition, which has both age- and sex-dependent effects on weight gain, on hypothalamic inflammation/gliosis. Although both male and female Wistar rats accumulate excessive fat mass as early as postnatal day (PND) 10 with neonatal overnutrition, no increase in hypothalamic cytokine levels, markers of astrocytes or microglia, or inflammatory signaling pathways were observed. At PND 50, no effect of neonatal overnutriton was found in either sex, whereas at PND 150, males again weighed significantly more than their controls, and this was coincident with an increase in markers of inflammation and astrogliosis in the hypothalamus. Circulating triglycerides and free fatty acids were also elevated in these males, but not in females or in either sex at PND 10. Thus, the effects of fatty acids and estrogens on astrocytes in vitro were analyzed. Our results indicate that changes in circulating fatty acid levels may be involved in the induction of hypothalamic inflammation/gliosis in excess weight gain, even on a normal diet, and that estrogens could participate in the protection of females from these processes. In conclusion, the interaction of developmental influences, dietary composition, age, and sex determines the central inflammatory response and the associated long-term outcomes of excess weight gain.
Assuntos
Astrócitos/metabolismo , Gliose/etiologia , Hiperfagia/fisiopatologia , Doenças Hipotalâmicas/etiologia , Hipotálamo/metabolismo , Microglia/metabolismo , Adiposidade , Fatores Etários , Animais , Animais Recém-Nascidos , Astrócitos/imunologia , Astrócitos/patologia , Biomarcadores/metabolismo , Células Cultivadas , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Gliose/imunologia , Gliose/metabolismo , Gliose/patologia , Doenças Hipotalâmicas/imunologia , Doenças Hipotalâmicas/metabolismo , Doenças Hipotalâmicas/patologia , Hipotálamo/imunologia , Hipotálamo/patologia , Mediadores da Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos Wistar , Caracteres Sexuais , Transdução de Sinais , Aumento de PesoRESUMO
The activation of resident microglial cells, alongside the infiltration of peripheral macrophages, are key neuroinflammatory responses to traumatic brain injury (TBI) that are directly associated with neuronal death. Sexual disparities in response to TBI have been previously reported; however it is unclear whether a sex difference exists in neuroinflammatory progression after TBI. We exposed male and female mice to moderate-to-severe controlled cortical impact injury and studied glial cell activation in the acute and chronic stages of TBI using immunofluorescence and in situ hybridization analysis. We found that the sex response was completely divergent up to 7 days postinjury. TBI caused a rapid and pronounced cortical microglia/macrophage activation in male mice with a prominent activated phenotype that produced both pro- (IL-1ß and TNFα) and anti-inflammatory (Arg1 and TGFß) cytokines with a single-phase, sustained peak from 1 to 7 days. In contrast, TBI caused a less robust microglia/macrophage phenotype in females with biphasic pro-inflammatory response peaks at 4 h and 7 days, and a delayed anti-inflammatory mRNA peak at 30 days. We further report that female mice were protected against acute cell loss after TBI, with male mice demonstrating enhanced astrogliosis, neuronal death, and increased lesion volume through 7 days post-TBI. Collectively, these findings indicate that TBI leads to a more aggressive neuroinflammatory profile in male compared with female mice during the acute and subacute phases postinjury. Understanding how sex affects the course of neuroinflammation following brain injury is a vital step toward developing personalized and effective treatments for TBI.
Assuntos
Lesões Encefálicas Traumáticas/imunologia , Inflamação/fisiopatologia , Caracteres Sexuais , Animais , Arginase/metabolismo , Astrócitos/imunologia , Astrócitos/patologia , Lesões Encefálicas Traumáticas/patologia , Morte Celular , Modelos Animais de Doenças , Feminino , Gliose/imunologia , Gliose/patologia , Inflamação/patologia , Ativação de Macrófagos/imunologia , Ativação de Macrófagos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/imunologia , Microglia/patologia , Neuroimunomodulação/fisiologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aß1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aß1-15 group, but did not reduce the ß-amyloid (Aß) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+ regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aß1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aß1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aß1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Vacina BCG/uso terapêutico , Encéfalo/imunologia , Monócitos/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Gliose/tratamento farmacológico , Gliose/imunologia , Gliose/patologia , Humanos , Interleucina-10/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Fragmentos de Peptídeos/imunologia , Baço/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
Sandhoff disease (SD) is caused by the loss of ß-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from Hexb mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. Hexb-/- mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. Hexb-/- mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16-18 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (Hexb-/-) were crossed to mice lacking an activating immune receptor (FcRγ-/-) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of Hexb-/- mice during the asymptomatic phase, and were inhibited in Hexb-/- FcRγ-/- mice. Moreover, early astrogliosis and impaired motor coordination in Hexb-/- mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD.