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1.
Neurochem Int ; 126: 139-153, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30867127

RESUMO

Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently showed that encephalitogenic lymphocytes are recruited to the sites of active demyelination induced by cuprizone. Here, we investigated whether cuprizone-induced oligodendrocyte and myelin pathology is sufficient to trigger peripheral immune cell recruitment into the forebrain. We show that early cuprizone-induced white matter lesions display a striking similarity to early MS lesions, i.e., oligodendrocyte degeneration, microglia activation and absence of severe lymphocyte infiltration. Such early cuprizone lesions are sufficient to trigger peripheral immune cell recruitment secondary to subsequent EAE (experimental autoimmune encephalomyelitis) induction. The lesions are characterized by discontinuation of the perivascular glia limitans, focal axonal damage, and perivascular astrocyte pathology. Time course studies showed that the severity of cuprizone-induced lesions positively correlates with the extent of peripheral immune cell recruitment. Furthermore, results of genome-wide array analyses suggest that moesin is integral for early microglia activation in cuprizone and MS lesions. This study underpins the significance of brain-intrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Imunidade Celular/fisiologia , Microglia/imunologia , Oligodendroglia/imunologia , Prosencéfalo/imunologia , Animais , Cuprizona/toxicidade , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Feminino , Imunidade Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Fragmentos de Peptídeos/toxicidade , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia
2.
J Neuroinflammation ; 16(1): 64, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894198

RESUMO

BACKGROUND: Orexins (hypocretins, Hcrt) A and B are GPCR-binding hypothalamic neuropeptides known to regulate sleep/wake states and feeding behavior. A few studies have shown that orexin A exhibits anti-inflammatory and neuroprotective properties, suggesting that it might provide therapeutic effects in inflammatory and neurodegenerative diseases like multiple sclerosis (MS). In MS, encephalitogenic Th1 and Th17 cells trigger an inflammatory response in the CNS destroying the myelin sheath. Here, we investigated the effects of peripheral orexin A administration to mice undergoing experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. METHODS: Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55 in CFA. Mice were treated intraperitoneally for five consecutive days with either PBS or 300 µg of orexin A starting at a moderate EAE score. Molecular, cellular, and histological analysis were performed by real-time PCR, ELISA, flow cytometry, and immunofluorescence. RESULTS: Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4+ T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-ß) expressions in the CNS. Moreover, orexin A treatment was neuroprotective, decreasing demyelination, astrogliosis, and microglial activation. Despite its strong local therapeutic effects, orexin A did not impair peripheral draining lymph node cell proliferation and Th1/Th17 cytokine production in response to MOG35-55 in vitro. CONCLUSIONS: Peripherally-administered orexin A ameliorated EAE by reducing CNS neuroinflammation. These results suggest that orexins may represent new therapeutic candidates that should be further investigated for MS treatment.


Assuntos
Anti-Inflamatórios/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Orexinas/administração & dosagem , Animais , Proliferação de Células/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , RNA Mensageiro/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fatores de Tempo
3.
Mult Scler Relat Disord ; 30: 225-230, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30825702

RESUMO

Neuromyelitis optica (NMO) is recognized as a different CNS autoimmune disease from multiple sclerosis (MS). Whether NMO-IgG contributes directly to the pathogenesis of NMO or is just a serologic marker of autoimmune responses of the disease needs to be clarified. We created MOG-induced experimental autoimmune encephalomyelitis (EAE) mice by passively transferring NMO-IgG to model the pathogenic findings in NMO patients. The mice were divided into three groups and administered intrathecal PBS, human complement with IgG from normal subjects, or IgG from AQP4(+) patients on days 8 and 11 after immunization. The EAE scores of EAE mice with intrathecal NMO-IgG injection were significantly elevated 14 days post-immunization. All of the mice were sacrificed for brain and spinal cord pathology analysis on day 21 post-immunization. Compared to mice given normal human IgG, EAE mice injected with NMO-IgG had markedly decreased AQP4 and glial fibrillary acidic protein (GFAP) expression and fluorescent intensity in the brain and spinal cord but more scattered deposition of complement (C9neo). Thus, our studies not only support the pathogenic role of NMO-IgG with complement in NMO disease but also provide a platform for the development of future therapeutics.


Assuntos
Aquaporina 4/imunologia , Encéfalo/patologia , Proteínas do Sistema Complemento/administração & dosagem , Imunoglobulina G/administração & dosagem , Medula Espinal/patologia , Análise de Variância , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Feminino , Adjuvante de Freund/toxicidade , Proteína Glial Fibrilar Ácida/metabolismo , Células HEK293 , Humanos , Injeções Espinhais , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Fatores de Tempo
4.
Pain ; 160(5): 1037-1049, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30649100

RESUMO

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with many known structural and functional changes in the central nervous system. A well-recognized, but poorly understood, complication of MS is chronic pain. Little is known regarding the influence of sex on the development and maintenance of MS-related pain. This is important to consider, as MS is a predominantly female disease. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we demonstrate sex differences in measures of spinal cord inflammation and plasticity that accompany tactile hypersensitivity. Although we observed substantial inflammatory activity in both sexes, only male EAE mice exhibit robust staining of axonal injury markers and increased dendritic arborisation in morphology of deep dorsal horn neurons. We propose that tactile hypersensitivity in female EAE mice may be more immune-driven, whereas pain in male mice with EAE may rely more heavily on neurodegenerative and plasticity-related mechanisms. Morphological and inflammatory differences in the spinal cord associated with pain early in EAE progression supports the idea of differentially regulated pain pathways between the sexes. Results from this study may indicate future sex-specific targets that are worth investigating for their functional role in pain circuitry.


Assuntos
Sistema Nervoso Central/fisiopatologia , Encefalomielite Autoimune Experimental/complicações , Plasticidade Neuronal/fisiologia , Dor/etiologia , Dor/patologia , Animais , Axônios/patologia , Axônios/ultraestrutura , Proteínas de Ligação ao Cálcio/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/ultraestrutura , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Ciclo Estral/fisiologia , Feminino , Adjuvante de Freund/toxicidade , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Atividade Motora/fisiologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Limiar da Dor/fisiologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Toxina Pertussis/toxicidade , Estimulação Física/efeitos adversos , Fatores Sexuais
5.
Glia ; 67(5): 857-869, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30548333

RESUMO

In the injured central nervous system, myeloid cells, including macrophages and microglia, are key contributors to both myelin injury and repair. This immense plasticity emphasizes the need to further understand the precise molecular mechanisms that contribute to the dynamic regulation of myeloid cell polarization and function. Herein, we demonstrate that miR-223 is upregulated in multiple sclerosis (MS) patient monocytes and the alternatively-activated and tissue-regenerating M2-polarized human macrophages and microglia. Using miR-223 knock-out mice, we observed that miR-223 is dispensable for maximal pro-inflammatory responses, but is required for efficient M2-associated phenotype and function, including phagocytosis. Using the lysolecithin animal model, we further demonstrate that miR-223 is required to efficiently clear myelin debris and promote remyelination. These results suggest miR-223 constrains neuroinflammation while also promoting repair, a finding of important pathophysiological relevance to MS as well as other neurodegenerative diseases.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , MicroRNAs/metabolismo , Células Mieloides/fisiologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Corpo Caloso/patologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/etiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/terapia , Modelos Animais de Doenças , Adjuvante de Freund/toxicidade , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lipopolissacarídeos/toxicidade , Lisofosfatidilcolinas/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Microglia/efeitos dos fármacos , Microglia/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Células Mieloides/metabolismo , Fragmentos de Peptídeos/toxicidade , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Espécies Reativas de Oxigênio/metabolismo
6.
Biochemistry ; 58(6): 763-775, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30513201

RESUMO

Multiple sclerosis (MS) is an autoimmune disorder manifested via chronic inflammation, demyelination, and neurodegeneration inside the central nervous system. The progressive phase of MS is characterized by neurodegeneration, but unlike classical neurodegenerative diseases, amyloid-like aggregation of self-proteins has not been documented. There is evidence that citrullination protects an immunodominant peptide of human myelin oligodendrocyte glycoprotein (MOG34-56) against destructive processing in Epstein-Barr virus-infected B-lymphocytes (EBV-BLCs) in marmosets and causes exacerbation of ongoing MS-like encephalopathies in mice. Here we collected evidence that citrullination of MOG can also lead to amyloid-like behavior shifting the disease pathogenesis toward neurodegeneration. We observed that an immunodominant MOG peptide, MOG35-55, displays amyloid-like behavior upon site-specific citrullination at positions 41, 46, and/or 52. These amyloid aggregates are shown to be toxic to the EBV-BLCs and to dendritic cells at concentrations favored for antigen presentation, suggesting a role of amyloid-like aggregation in the pathogenesis of progressive MS.


Assuntos
Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Linfócitos B/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Fragmentos de Peptídeos/metabolismo , Sequência de Aminoácidos , Amiloide/imunologia , Amiloide/toxicidade , Proteínas Amiloidogênicas/síntese química , Proteínas Amiloidogênicas/imunologia , Proteínas Amiloidogênicas/toxicidade , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/virologia , Benzotiazóis/química , Callithrix , Linhagem Celular , Citrulinação/imunologia , Células Dendríticas/metabolismo , Herpesvirus Humano 4 , Humanos , Camundongos Endogâmicos C57BL , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Crônica Progressiva/virologia , Glicoproteína Mielina-Oligodendrócito/síntese química , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Agregação Patológica de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/toxicidade , Linfócitos T/imunologia , Linfócitos T/metabolismo
7.
Glia ; 66(12): 2645-2658, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30306644

RESUMO

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell-mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 Δ/- mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC-sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.


Assuntos
Doenças do Sistema Nervoso Central/complicações , Inflamação/etiologia , Inflamação/patologia , Proteínas de Membrana/metabolismo , Microglia/metabolismo , Microglia/patologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Proteínas de Ligação ao Cálcio , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Endonucleases/genética , Endonucleases/metabolismo , Feminino , Adjuvante de Freund/toxicidade , Expressão Gênica/fisiologia , Humanos , Lipopolissacarídeos/farmacologia , Macaca mulatta , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos , Microglia/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/toxicidade
8.
J Neuroinflammation ; 15(1): 296, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367633

RESUMO

BACKGROUND: Recent studies in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), suggest an involvement of the histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in important processes such as cell adhesion and migration. METHODS: Here, we aimed to expand these initial observations by investigating the role of EZH2 in MS. mRNA expression levels for EZH2 were measured by real-time PCR in peripheral blood mononuclear cells (PBMC) from 121 MS patients (62 untreated and 59 receiving treatment) and 24 healthy controls. RESULTS: EZH2 expression levels were decreased in PBMC from untreated patients compared to that from controls, and treatment significantly upregulated EZH2 expression. Expression of miR-124 was increased in MS patients compared to controls. Blood immunophenotyping revealed EZH2 expression mostly restricted to CD4+ and CD8+ T cells, and circulating EZH2+ CD4+ and CD8+ T cells were decreased in untreated MS patients compared to controls. CD8+ T cells expressing EZH2 exhibited a predominant central memory phenotype, whereas EZH2+ CD4+ T cells were of effector memory nature, and both T cell subsets produced TNF-α. EZH2+ T cells were enriched in the cerebrospinal fluid compartment compared to blood and were found in chronic active lesions from MS patients. EZH2 inhibition and microarray analysis in PBMC was associated with significant downregulation of key T cell adhesion molecules. CONCLUSION: These findings suggest a role of EZH2 in the migration of T cells in MS patients. The observation of TNF-α expression by CD4+ and CD8+ T cells expressing EZH2 warrants additional studies to explore more in depth the pathogenic potential of EZH2+-positive cells in MS.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Leucócitos Mononucleares/metabolismo , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Adulto , Animais , Estudos de Coortes , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Adjuvante de Freund/toxicidade , Humanos , Leucócitos Mononucleares/classificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Subpopulações de Linfócitos T , Talina/genética , Talina/metabolismo , Adulto Jovem
9.
Glia ; 66(12): 2589-2603, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30325069

RESUMO

Gap junctions (GJs) coupling oligodendrocytes to astrocytes and to other oligodendrocytes are formed mainly by connexin47 (Cx47) and a smaller portion by connexin32 (Cx32). Mutations in both connexins cause inherited demyelinating disorders, but their expression is also disrupted in multiple sclerosis (MS). To clarify whether the loss of either Cx47 or Cx32 could modify the outcome of inflammation and myelin loss, we induced experimental autoimmune encephalomyelitis (EAE) in fully backcrossed Cx32 knockout (KO) and Cx47KO mice and compared their outcome with wild type (WT, C57BI/6 N) mice. Cx47KO EAE mice developed the most severe phenotype assessed by clinical scores and behavioral testing, followed by Cx32KO and WT mice. Cx47KO more than Cx32KO EAE mice developed more microglial activation, myelin, and axonal loss than did WT mice. Oligodendrocyte apoptosis and precursor proliferation was also higher in Cx47KO than in Cx32KO or WT EAE mice. Similarly, blood-spinal cord barrier (BSCB) disruption and inflammatory infiltrates of macrophages, T- and B-cells were more severe in Cx47KO than either Cx32KO or WT EAE groups. Finally, expression profiling revealed that several proinflammatory cytokines were higher at the peak of inflammation in the Cx47KO mice and persisted at later stages of EAE in contrast to reduction of their levels in WT EAE mice. Thus, loss of oligodendrocyte GJs aggravates BSCB disruption and inflammatory myelin loss, likely due to dysregulation of proinflammatory cytokines. This mechanism may play an important role in MS brain with reduced connexin expression, as well as in patients with inherited mutations in oligodendrocyte connexins and secondary inflammation.


Assuntos
Citocinas/metabolismo , Encefalomielite Autoimune Experimental/patologia , Junções Comunicantes/metabolismo , Regulação da Expressão Gênica/fisiologia , Força da Mão/fisiologia , Oligodendroglia/metabolismo , Animais , Apoptose/genética , Astrócitos/metabolismo , Astrócitos/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células/genética , Conexinas/genética , Conexinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/fisiopatologia , Adjuvante de Freund/toxicidade , Junções Comunicantes/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Glicoproteína Mielina-Oligodendrócito/toxicidade , Oligodendroglia/patologia , Fragmentos de Peptídeos/toxicidade
10.
J Neuroinflammation ; 15(1): 270, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231889

RESUMO

BACKGROUND: Axonal degeneration and neuronal loss have been described as the major causes of irreversible clinical disability in multiple sclerosis (MS). The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) protein has been associated with neuroprotection in models of ischemia and neuronal responses to stressors. METHODS: To characterize its potential to influence inflammatory neurodegeneration, we examined ARNT2 expression in the experimental autoimmune encephalomyelitis (EAE) model of MS and characterized mediators that influence ARNT2 expression as well as plausible partners and targets. RESULTS: Arnt2 message and protein levels dropped significantly in EAE spinal cords as disease developed and were lowest at peak disability. ARNT2 expression is prominent in neuronal cell bodies within the gray matter with some staining in glial fibrillary acidic protein (GFAP)+ astrocytes in healthy animals. At peak disease, ARNT2 expression is reduced by 20-50% in gray matter neurons compared to healthy controls. ARNT2 intensity in neurons throughout the EAE spinal cord correlated inversely with the degree of immune cell infiltration (r = - 0.5085, p < 0.01) and axonal damage identified with SMI32 staining (r = - 0.376, p = 0.032). To understand the relationship between ARNT2 expression and neuronal health, we exposed enriched cortical cultures of neurons to hydrogen peroxide (H2O2) to mimic oxidative stress. H2O2 at lower doses rapidly increased ARNT2 protein levels which returned to baseline within 3-4 h. Exposure to higher doses of H2O2) dropped ARNT2 levels below baseline, preceding cytotoxicity measured by morphological changes and lactate dehydrogenase release from cells. Decreases in ARNT2 secondary to staurosporine and H2O2 preceded increases in cleaved caspase 3 and associated apoptosis. We also examined expression of neuronal pas 4 (Npas4), whose heterodimerization with ARNT2 drives expression of the neurotrophic factor brain-derived neurotrophic factor (Bdnf). Like ARNT2, Npas4 levels also decline at the onset of EAE and are linked to decreases in Bdnf. In vitro, H2O2 exposure drives Npas4 expression that is tied to increases in Bdnf. CONCLUSION: Our data support ARNT2 as a neuronal transcription factor whose sustained expression is linked to neuronal and axonal health, protection that may primarily be driven through its partnering with Npas4 to influence BDNF expression.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação da Expressão Gênica/fisiologia , Esclerose Múltipla/complicações , Neurônios/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Axônios/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Progressão da Doença , Embrião de Mamíferos , Feminino , Adjuvante de Freund/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Toxina Pertussis/toxicidade
11.
J Neuropathol Exp Neurol ; 77(11): 1024-1038, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252090

RESUMO

Neuron-derived molecules are potent regulators of oligodendrocyte differentiation and myelination during brain development and upon demyelination. Their analysis will thus contribute to understanding remyelination failure in demyelinating diseases, such as multiple sclerosis (MS). Previously, we have identified neuronal galectin-4 as a novel negative soluble regulator in the timing of developmental myelination. Here, we investigated whether galectin-4 is re-expressed in axons upon demyelination to regulate the timing of remyelination. Our findings revealed that galectin-4 is transiently localized to axons in demyelinated areas upon cuprizone-induced demyelination. In contrast, in chronic demyelinated MS lesions, where remyelination fails, galectin-4 is permanently present on axons. Remarkably, microglia/macrophages in cuprizone-demyelinated areas also harbor galectin-4, as also observed in activated microglia/macrophages that are present in active MS lesions and in inflammatory infiltrates in chronic-relapsing experimental autoimmune encephalomyelitis. In vitro analysis showed that galectin-4 is effectively endocytosed by macrophages, and may scavenge galectin-4 from oligodendrocytes, and that endogenous galectin-4 levels are increased in alternatively interleukin-4-activated macrophages and microglia. Hence, similar to developmental myelination, the (re)expressed galectin-4 upon demyelination may act as factor in the timing of oligodendrocyte differentiation, while the persistent presence of galectin-4 on demyelinated axons may disrupt this fine-tuning of remyelination.


Assuntos
Axônios/metabolismo , Encéfalo/patologia , Galectina 4/metabolismo , Macrófagos/efeitos dos fármacos , Microglia/patologia , Esclerose Múltipla/patologia , Animais , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Cuprizona/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Galectina 4/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Lectinas/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Inibidores da Monoaminoxidase/toxicidade , Esclerose Múltipla/induzido quimicamente , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , RNA Mensageiro/metabolismo , Ratos , Fatores de Tempo
12.
Nat Neurosci ; 21(10): 1380-1391, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224810

RESUMO

Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.


Assuntos
Encefalite/patologia , Encefalite/fisiopatologia , Vasos Linfáticos/fisiologia , Meninges/patologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Fármacos Fotossensibilizantes/farmacologia , Receptores CCR7/deficiência , Receptores CCR7/genética , Baço/patologia , Linfócitos T/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
13.
J Neuroinflammation ; 15(1): 236, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30134924

RESUMO

BACKGROUND: Very late antigen 4 (VLA-4; integrin α4ß1) is critical for transmigration of T helper (TH) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). We have previously shown that VLA-4 and melanoma cell adhesion molecule (MCAM) are important for trans-endothelial migration of human TH17 cells in vitro and here investigate their contribution to pathogenic CNS inflammation. METHODS: Antibody blockade of VLA-4 and MCAM is assessed in murine models of CNS inflammation in conjunction with conditional ablation of α4-integrin expression in T cells. Effects of VLA-4 and MCAM blockade on lymphocyte migration are further investigated in the human system via in vitro T cell transmigration assays. RESULTS: Compared to the broad effects of VLA-4 blockade on encephalitogenic T cell migration over endothelial barriers, MCAM blockade impeded encephalitogenic T cell migration in murine models of MS that especially depend on CNS migration across the choroid plexus (CP). In transgenic mice lacking T cell α4-integrin expression (CD4::Itga4-/-), MCAM blockade delayed disease onset. Migration of MCAM-expressing T cells through the CP into the CNS was restricted, where laminin 411 (composed of α4, ß1, γ1 chains), the proposed major ligand of MCAM, is detected in the endothelial basement membranes of murine CP tissue. This finding was translated to the human system; blockade of MCAM with a therapeutic antibody reduced in vitro transmigration of MCAM-expressing T cells across a human fibroblast-derived extracellular matrix layer and a brain-derived endothelial monolayer, both expressing laminin α4. Laminin α4 was further detected in situ in CP endothelial-basement membranes in MS patients' brain tissue. CONCLUSIONS: Our findings suggest that MCAM-laminin 411 interactions facilitate trans-endothelial migration of MCAM-expressing T cells into the CNS, which seems to be highly relevant to migration via the CP and to potential future clinical applications in neuroinflammatory disorders.


Assuntos
Antígeno CD146/metabolismo , Plexo Corióideo/patologia , Encefalomielite Autoimune Experimental/patologia , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos/uso terapêutico , Antígeno CD146/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Sistema Nervoso Central/patologia , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Humanos , Integrina alfa4beta1/genética , Integrina alfa4beta1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Proteínas Quinases/genética , Proteínas Quinases/metabolismo
14.
J Neuroinflammation ; 15(1): 208, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012158

RESUMO

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated. METHODS: The spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry. RESULTS: CNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ. CONCLUSIONS: We provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations.


Assuntos
Encéfalo/metabolismo , Quimiocina CXCL2/metabolismo , Encefalomielite Autoimune Experimental/patologia , Interferon gama/metabolismo , Transdução de Sinais/fisiologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Proteína Glial Fibrilar Ácida/metabolismo , Interferon gama/genética , Interferon gama/farmacologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Células Mieloides/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Tecido Parenquimatoso/patologia , Fragmentos de Peptídeos/toxicidade , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Sci China Life Sci ; 61(6): 675-687, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29931449

RESUMO

GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54-/- mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54-/- mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis (EAE) developed in the Gpr54-/- mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54-/- mice compared to the respective wild-type control, suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Receptores de Kisspeptina-1/deficiência , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Expressão Gênica , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/toxicidade , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/fisiologia , Baço/imunologia , Timo/imunologia
16.
J Neuroinflammation ; 15(1): 183, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29903027

RESUMO

BACKGROUND: The oral immunomodulatory agent laquinimod is currently evaluated for multiple sclerosis (MS) treatment. Phase II and III studies demonstrated a reduction of degenerative processes. In addition to anti-inflammatory effects, laquinimod might have neuroprotective properties, but its impact on the visual system, which is often affected by MS, is unknown. The aim of our study was to investigate potential protective effects of laquinimod on the optic nerve and retina in an experimental autoimmune encephalomyelitis (EAE) model. METHODS: We induced EAE in C57/BL6 mice via MOG35-55 immunization. Animals were divided into an untreated EAE group, three EAE groups receiving laquinimod (1, 5, or 25 mg/kg daily), starting the day post-immunization, and a non-immunized control group. Thirty days post-immunization, scotopic electroretinograms were carried out, and mice were sacrificed for histopathology (HE, LFB), immunohistochemistry (MBP, Iba1, Tmem119, F4/80, GFAP, vimentin, Brn-3a, cleaved caspase 3) of the optic nerve and retina, and retinal qRT-PCR analyses (Brn-3a, Iba1, Tmem119, AMWAP, CD68, GFAP). To evaluate the effect of a therapeutic approach, EAE animals were treated with 25 mg/kg laquinimod from day 16 when 60% of the animals had developed clinical signs of EAE. RESULTS: Laquinimod reduced neurological EAE symptoms and improved the neuronal electrical output of the inner nuclear layer compared to untreated EAE mice. Furthermore, cellular infiltration, especially recruited phagocytes, and demyelination in the optic nerve were reduced. Microglia were diminished in optic nerve and retina. Retinal macroglial signal was reduced under treatment, whereas in the optic nerve macroglia were not affected. Additionally, laquinimod preserved retinal ganglion cells and reduced apoptosis. A later treatment with laquinimod in a therapeutic approach led to a reduction of clinical signs and to an improved b-wave amplitude. However, no changes in cellular infiltration and demyelination of the optic nerves were observed. Also, the number of retinal ganglion cells remained unaltered. CONCLUSION: From our study, we deduce neuroprotective and anti-inflammatory effects of laquinimod on the optic nerve and retina in EAE mice, when animals were treated before any clinical signs were noted. Given the fact that the visual system is frequently affected by MS, the agent might be an interesting subject of further neuro-ophthalmic investigations.


Assuntos
Encefalomielite Autoimune Experimental/patologia , Nervo Óptico/efeitos dos fármacos , Quinolonas/uso terapêutico , Retina/efeitos dos fármacos , Animais , Antígenos de Diferenciação/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrorretinografia , Encefalomielite Autoimune Experimental/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nervo Óptico/metabolismo , Nervo Óptico/fisiopatologia , Fragmentos de Peptídeos/toxicidade , Fagócitos/efeitos dos fármacos , RNA Mensageiro , Retina/metabolismo , Retina/fisiopatologia
17.
Brain ; 141(4): 1094-1110, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29506186

RESUMO

Multiple sclerosis presents with profound changes in the network of molecules involved in maintaining central nervous system architecture, the extracellular matrix. The extracellular matrix components, particularly the chondroitin sulfate proteoglycans, have functions beyond structural support including their potential interaction with, and regulation of, inflammatory molecules. To investigate the roles of chondroitin sulfate proteoglycans in multiple sclerosis, we used the experimental autoimmune encephalomyelitis model in a time course study. We found that the 4-sulfated glycosaminoglycan side chains of chondroitin sulfate proteoglycans, and the core protein of a particular family member, versican V1, were upregulated in the spinal cord of mice at peak clinical severity, correspondent with areas of inflammation. Versican V1 expression in the spinal cord rose progressively over the course of experimental autoimmune encephalomyelitis. A particular structure in the spinal cord and cerebellum that presented with intense upregulation of chondroitin sulfate proteoglycans is the leucocyte-containing perivascular cuff, an important portal of entry of immune cells into the central nervous system parenchyma. In these inflammatory perivascular cuffs, versican V1 and the glycosaminoglycan side chains of chondroitin sulfate proteoglycans were observed by immunohistochemistry within and in proximity to lymphocytes and macrophages as they migrated across the basement membrane into the central nervous system. Expression of versican V1 transcript was also documented in infiltrating CD45+ leucocytes and F4/80+ macrophages by in situ hybridization. To test the hypothesis that the chondroitin sulfate proteoglycans regulate leucocyte mobility, we used macrophages in tissue culture studies. Chondroitin sulfate proteoglycans significantly upregulated pro-inflammatory cytokines and chemokines in macrophages. Strikingly, and more potently than the toll-like receptor-4 ligand lipopolysaccharide, chondroitin sulfate proteoglycans increased the levels of several members of the matrix metalloproteinase family, which are implicated in the capacity of leucocytes to cross barriers. In support, the migratory capacity of macrophages in vitro in a Boyden chamber transwell assay was enhanced by chondroitin sulfate proteoglycans. Finally, using brain specimens from four subjects with multiple sclerosis with active lesions, we found chondroitin sulfate proteoglycans to be associated with leucocytes in inflammatory perivascular cuffs in all four patients. We conclude that the accumulation of chondroitin sulfate proteoglycans in the perivascular cuff in multiple sclerosis and experimental autoimmune encephalomyelitis boosts the activity and migration of leucocytes across the glia limitans into the central nervous system parenchyma. Thus, chondroitin sulfate proteoglycans represent a new class of molecules to overcome in order to reduce the inflammatory cascades and clinical severity of multiple sclerosis.


Assuntos
Encéfalo/patologia , Proteoglicanas de Sulfatos de Condroitina/farmacologia , Encefalomielite Autoimune Experimental/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Medula Espinal/patologia , Animais , Encéfalo/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Adjuvante de Freund/toxicidade , Laminina/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , RNA Mensageiro/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Versicanas/genética , Versicanas/metabolismo
18.
Genomics ; 110(6): 337-346, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29366861

RESUMO

Long non-coding RNAs have the potential to regulate immune responses. Their impact on multiple sclerosis has remained elusive. For illustrating their roles in experimental autoimmune encephalomyelitis (EAE) pathogenesis, we investigated the differential expression of lncRNAs and mRNAs in CD4+Th cells obtained from myelin oligodendrocytic glycoprotein35-55(MOG35-55)-induced EAE and complete Freund's adjuvant (CFA) controls. We observed differential expression of 1112 lncRNAs and 519 mRNAs in CD4+Th cells. The functional network showed lncRNAs had the capacity to modulate EAE pathogenesis via regulating many known EAE regulators such as Ptpn6. Predicting the function of lncRNAs demonstrated that dysregulated lncRNAs were closely associated with the development of EAE. These dysregulated lncRNAs may have function in EAE and they could be novel biomarkers and therapeutic targets of EAE. However, the precise mechanisms and biological functions of these specific lncRNAs in EAE pathogenesis require further study.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Encefalomielite Autoimune Experimental/genética , Feminino , Perfilação da Expressão Gênica , Camundongos , Glicoproteína Mielina-Oligodendrócito/farmacologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos
19.
Biomed Pharmacother ; 97: 557-563, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29101799

RESUMO

Multiple sclerosis (MS) is a deleterious autoimmune and demyelinating disorder of the central nervous system with debilitating sensory and motor complications. There is still no definite cure for it and the main focus for its treatment mostly pivots around subsiding its severity and recurrence. Experimental autoimmune encephalomyelitis (EAE) is an established animal model of MS. S-allyl cysteine (SAC) is the active and main constituent of aged garlic extract with anti-inflammatory and neuroprotective property. This study was conducted to evaluate its possible protective effect in EAE model of MS. SAC was administered p.o. at a dose of 50 mg/kg/day to female C57BL/6 mice immunized with myelin oligodendrocytic glycoprotein (MOG35-55). Results showed that SAC is capable to alleviate clinical signs and severity of the disease and improved lumbar spinal cord tissue level of tumor necrosis factor α (TNFa), interleukin 17 (IL-17), activity-dependent neuroprotector homeobox (ADNP), microtubule-associated proteins 1A/1 B light chain 3A (MAP1LC3A), and matrix metalloproteinase 9 (MMP-9). In addition, SAC attenuated inflammatory cell infiltration, axonal demyelination, and axonal loss in lumbar spinal cord in EAE group, as demonstrated by H & E, Luxol fast blue (LFB), and Bielschowsky silver staining, respectively. Taken together, SAC could mitigate severity of MOG35-55-induced EAE as a valid model of MS via amelioration of pathogenic molecular mechanisms responsible for neuroinflammation and axonal damage.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cisteína/análogos & derivados , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Animais , Anti-Inflamatórios/farmacologia , Cisteína/farmacologia , Cisteína/uso terapêutico , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/toxicidade
20.
eNeuro ; 5(6)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30627663

RESUMO

Treatments to stop gray matter degeneration are needed to prevent progressive disability in multiple sclerosis (MS). We tested whether inhibiting mixed-lineage kinases (MLKs), which can drive inflammatory microglial activation and neuronal degeneration, could protect hippocampal synapses in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates the excitatory synaptic injury that occurs widely within the gray matter in MS. URMC-099, a broad spectrum MLK inhibitor with additional activity against leucine-rich repeat kinase 2 (LRRK2) and other kinases, prevented loss of PSD95-positive postsynaptic structures, shifted activated microglia toward a less inflammatory phenotype, and reversed deficits in hippocampal-dependent contextual fear conditioning in EAE mice when administered after the onset of motor symptoms. A narrow spectrum inhibitor designed to be highly selective for MLK3 failed to protect synapses in EAE hippocampi, and could not rescue cultured neurons from trophic deprivation in an in vitro model of MLK-driven neuronal degeneration. These results suggest that URMC-099 may have potential as a neuroprotective treatment in MS and demonstrate that a broad spectrum of inhibition against a combination of MLK and other kinases is more effective in neuroinflammatory disease than selectively targeting a single kinase.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Hipocampo/patologia , Fármacos Neuroprotetores/uso terapêutico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Sinapses/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/fisiopatologia , Inibidores Enzimáticos/uso terapêutico , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Gânglio Cervical Superior/citologia
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