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1.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600882

RESUMO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Mitocôndrias/metabolismo , Esclerose Múltipla/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/etiologia , Feminino , Camundongos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Músculo Esquelético/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
2.
Iran J Allergy Asthma Immunol ; 18(3): 230-250, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522431

RESUMO

Toll-like receptors (TLRs) play principle roles in recognition of autologous components which have been pointed as the danger-associated molecular patterns (DAMP) and microbial components which are identified as pathogen associated molecular patterns (PAMP).The infiltration of various inflammatory cells such as dendritic cells, lymphocytes (CD4+ T, CD8+ T as well as B cells), monocytes and macrophages occur into the central nervous sys-tem (CNS) during multiple sclerosis (MS) and its animal model named experimental autoimmune encephalomyelitis (EAE). The infiltrated leukocytes and residential cells of the CNS express several TLRs (especially TLR2) and their expression are elevated in MS and EAE. TLR2 recognizes a large variety DAMP and PAMP molecules due to its ability to create heterodimers with TLR1, TLR6 and probably TLR10. A wide spectrum of  DAMP molecules, including heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), ß-defensin 3, surfactant protein A and D, eosinophil-derived neurotoxin, gangliosides, serum amyloid A, hyaluronic acid and biglycan are identified by TLR2, whose their expression is increased in MS patients. TLR2 may contribute in the development of MS and EAE diseases through the reinforcement of Th1/Th17 cell-related responses, downregulation of regulatory T cells, induction of IL-17+ γδ T cells, inhibition of oligodendrocyte maturation, induction of poly ADP-ribose polymerase-1 (PARP-1)-dependent pathway in microglia, macrophages and astrocytes and inhibition of type I interferons expression. The contribution of TLR2-related immunopathological responses in the MS and EAE pathogenesis and its possible targeting as promising therapeutic potentials are considered in this review.


Assuntos
Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Comunicação Celular , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/metabolismo , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética
3.
Iran J Allergy Asthma Immunol ; 18(3): 300-309, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522437

RESUMO

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system.MS creates a wide range of symptoms with lifelong debilitating consequences. The hallmark of the disease is the inflammation of the nervous system, which can lead to damage to the nerve tissue and loss of function of the neurons. IL-17 has a prominent role in the beginning of inflammatory reactions. Here, we analyzed a mouse model developed using anti-myelin antibodies. This mouse model mimics many symptoms of MS in humans. C57BL/6 mice were randomly divided into five groups. Mice were immunized subcutaneously with 50 µg, 100 µg, 150 µg and 200 µg myelin oligodendrocyte glycoprotein in complete Freund's adjuvant containing 4 mg/Ml Mycobacterium tuberculosis and two injections of 800 ng of pertussis toxin intraperitoneally, on day 0 and 2 post immunization. Serum level of IL-17 was measured, inflammation and demyelination of brain tissue were also evaluated. Mice with experimental autoimmune encephalomyelitis demonstrated inflammatory cell accumulation, different degrees of demyelination in the brain, and rising levels of serum IL-17 depending on the dose of the anti-myelin antibody. Our study demonstrates that level of IL-17 production is directly associated with inflammation and demyelination. In addition, different degrees of experimental autoimmune encephalomyelitis in mice can be utilized to test a wide range of therapeutic interventions for MS treatment.


Assuntos
Encéfalo/imunologia , Encéfalo/metabolismo , Doenças Desmielinizantes/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Interleucina-17/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Animais , Encéfalo/patologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/diagnóstico , Feminino , Imuno-Histoquímica , Camundongos , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Índice de Gravidade de Doença
4.
Folia Neuropathol ; 57(2): 117-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556572

RESUMO

Previous studies have shown that Huangqi glycoprotein (HQGP) has an anti-inflammatory effect in vitro, and suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, the mechanism underlying its effect is largely unknown. In this manuscript we investigated the mechanisms by which HQGP protect mice from EAE. HQGP was extracted from Astragalus membranaceus and purified by anion-exchange and gel filtration chromatography. HQGP delayed disease onset, reduced disease severity and alleviated inflammation and demyelination in the central nervous system (CNS). Moreover, HQGP reduced the infiltration of pathogenic immune cells and increased the expression of microtubule-associated protein 2 (MAP-2) and neuronal nuclei (NeuN) in the CNS. HQGP treatment also reduced the expression of chemokines such as CCL2 and CCL5 and the production of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, but increased the level of IL-10. These results demonstrate that HQGP suppressed EAE development by modulating the immune system and the infiltration of leukocytes to the CNS as well as promoting axon and neural repair.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Camundongos , Fármacos Neuroprotetores/farmacologia , Índice de Gravidade de Doença
5.
Folia Neuropathol ; 57(2): 129-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556573

RESUMO

Repetitive transcranial magnetic stimulation (rTMS) induces changes in expression of proteins engaged in the activity of excitatory and inhibitory systems, restores these functions and suppresses the progression of disability in experimental autoimmune encephalitis (EAE). The structural type of TMS, the arrangement as theta burst stimulation (TBS) has been applied as intermittent TBS (iTBS) and continuous TBS (cTBS) protocols to female adult DA rats. The animals were randomly divided into experimental groups: control group (C), group treated with complete Freund's adjuvant (CFA), experimental autoimmune encephalomyelitis (EAE) group, group treated with iTBS post EAE immunization (EAE + iTBS), group treated with cTBS post EAE immunization (EAE + cTBS), group of healthy animals treated with iTBS or cTBS. Therapeutic protocols of iTBS or cTBS in all EAE groups of animals were performed starting from 14 days post immunization (dpi), for 10 days with time point decapitation at 24 dpi. After decapitation, spinal cords were analysed for BDNF and Ki67 expression. The results revealed reduced BDNF expression in the rat's spinal cord of EAE animals in the stage of remission, which was associated with increased Ki67 and GFAP expressions. Decreased Iba 1 and BDNF expression, contrary to increased Iba 1 and Ki67 expression, suggests clustered microglia in the resolution phase of EAE. Enhanced GABA expression in spinal cord sections indicates higher GABA metabolic turnover, and also GAD activity in astrocytes, or prominent activity of GABAergic neurons. Both TBS protocols induced advance BDNF expression; amongst iTBS application provoked elevating of BDNF and stabilizing of GFAP and Ki67 expressions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/terapia , Medula Espinal/metabolismo , Estimulação Magnética Transcraniana/métodos , Animais , Astrócitos/metabolismo , Progressão da Doença , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Ratos
6.
Nat Rev Neurol ; 15(12): 704-717, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31527807

RESUMO

Immune cells mediate critical inflammatory and neurodegenerative processes in the CNS in individuals with multiple sclerosis (MS). In MS, activated microglia, border-associated macrophages and monocyte-derived macrophages in the CNS can encounter T cells that have infiltrated the brain parenchyma from the circulation. Although microglia and T cells both contribute to normal CNS development and homeostasis, evidence suggests that the meeting of activated microglia and macrophages with encephalitogenic T cells exacerbates their capacity to inflict injury. This crosstalk involves many cell-surface molecules, cytokines and neurotoxic factors. In this Review, we summarize the mechanisms and consequences of T cell-microglia interactions as identified with in vitro experiments and animal models, and discuss the challenges that arise when translating this preclinical knowledge to MS in humans. We also consider therapeutic approaches to MS of which the mechanisms involve prevention or modulation of T cell and microglia responses and their interactions.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Microglia/imunologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Animais , Comunicação Celular/fisiologia , Encefalomielite Autoimune Experimental/metabolismo , Homeostase/fisiologia , Humanos , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Linfócitos T/metabolismo
7.
Immunol Res ; 67(2-3): 223-240, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31396845

RESUMO

Pharmacological blockade of α1-adrenoceptor is shown to influence development of experimental autoimmune encephalomyelitis (EAE), an IL-17-producing CD4+TCR+ (Th17) cell-mediated disease mimicking multiple sclerosis. Considering significance of CD4+ cell priming for the clinical outcome of EAE, the study examined α1-adrenoceptor-mediated influence of catecholamines, particularly those derived from draining lymph node (dLN) cells (as catecholamine supply from nerve fibers decreases with the initiation of autoimmune diseases) for CD4+ cell priming. The results confirmed diminishing effect of immunization on nerve fiber-derived noradrenaline supply and showed that antigen presenting and CD4+ cells synthesize catecholamines, while antigen presenting cells and only CD4+CD25+Foxp3+ regulatory T cells (Tregs) express α1-adrenoceptor. The analysis of influence of α1-adrenoceptor antagonist prazosin on the myelin basic protein (MBP)-stimulated CD4+ lymphocytes in dLN cell culture showed their diminished proliferation in the presence of prazosin. This was consistent with prazosin enhancing effect on Treg frequency and their Foxp3 expression in these cultures. The latter was associated with upregulation of TGF-ß expression. Additionally, prazosin decreased antigen presenting cell activation and affected their cytokine profile by diminishing the frequency of cells that produce Th17 polarizing cytokines (IL-1ß and IL-23) and increasing that of IL-10-producing cells. Consistently, the frequency of all IL-17A+ cells and those co-expressing GM-CSF within CD4+ lymphocytes was decreased in prazosin-supplemented MBP-stimulated dLN cell cultures. Collectively, the results indicated that dLN cell-derived catecholamines may influence EAE development by modulating interactions between distinct subtypes of CD4+ T cells and antigen presenting cells through α1-adrenoceptor and consequently CD4+ T cell priming.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Norepinefrina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Imunização , Imunofenotipagem , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária/genética , Masculino , Ratos , Receptores Adrenérgicos alfa 1/genética , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/metabolismo
8.
J Neuroinflammation ; 16(1): 167, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31416452

RESUMO

BACKGROUND: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. METHODS: In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35-55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load. RESULTS: Treatment of MOG35-55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35-55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35-55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. CONCLUSIONS: Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.


Assuntos
Células Dendríticas/metabolismo , Eletroporação/métodos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/terapia , Glicoproteína Mielina-Oligodendrócito/metabolismo , RNA Mensageiro/metabolismo , Animais , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Tolerância Imunológica/fisiologia , Células K562 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , RNA Mensageiro/administração & dosagem , RNA Mensageiro/imunologia
9.
J Neuroinflammation ; 16(1): 161, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362762

RESUMO

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). It is firmly established that overactivation of the p65 (RelA) nuclear factor kappa B (NF-κB) transcription factor upregulates expression of inflammatory mediators in both immune and non-immune resident CNS cells and promotes inflammation during MS. In contrast to p65, NF-κB family member RelB regulates immune cell development and can limit inflammation. Although RelB expression is induced during inflammation in the CNS, its role in MS remains unknown. METHODS: To examine the role of RelB in non-immune CNS cells, we generated mice with RelB specifically deleted in astrocytes (RelBΔAST), oligodendrocytes (RelBΔOLIGO), or neural progenitor-derived cells (RelBΔNP). We used experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS, to assess the effect of RelB deletion on disease outcomes and performed analysis on the histological, cellular, and molecular level. RESULTS: Despite being a negative regulator of inflammation, conditional knockout of RelB in non-immune resident CNS cells surprisingly decreased the severity of EAE. This protective effect was recapitulated by conditional deletion of RelB in oligodendrocytes but not astrocytes. Deletion of RelB in oligodendrocytes reduced disease severity, promoted survival of mature oligodendrocytes, and correlated with increased activation of p65 NF-κB. CONCLUSIONS: These findings suggest that RelB fine tunes inflammation and cell death/survival during EAE. Importantly, our data points out the detrimental role RelB plays in controlling survival of mature oligodendrocytes, which could be explored as a viable option to treat MS in the future.


Assuntos
Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Oligodendroglia/metabolismo , Fator de Transcrição RelB/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/patologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , NF-kappa B/metabolismo , Células-Tronco Neurais/metabolismo , Fator de Transcrição RelB/genética
10.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426440

RESUMO

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases which are secreted or anchored in the cell membrane and are capable of degrading the multiple components of the extracellular matrix (ECM). MMPs are frequently overexpressed or highly activated in numerous human diseases. Owing to the important role of MMPs in human diseases, many MMP inhibitors (MMPIs) have been developed as novel therapeutics, and some of them have entered clinical trials. However, so far, only one MMPI (doxycycline) has been approved by the FDA. Therefore, the evaluation of the activity of a specific subset of MMPs in human diseases using clinically relevant imaging techniques would be a powerful tool for the early diagnosis and assessment of the efficacy of therapy. In recent years, numerous MMPIs labeled imaging agents have emerged. This article begins by providing an overview of the MMP subfamily and its structure and function. The latest advances in the design of subtype selective MMPIs and their biological evaluation are then summarized. Subsequently, the potential use of MMPI-labeled diagnostic agents in clinical imaging techniques are discussed, including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging (OI). Finally, this article concludes with future perspectives and clinical utility.


Assuntos
Aterosclerose/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Inibidores de Metaloproteinases de Matriz/farmacocinética , Metaloproteinases da Matriz/química , Sondas Moleculares/farmacocinética , Neoplasias/diagnóstico por imagem , Osteoartrite/diagnóstico por imagem , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Domínio Catalítico/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Pneumopatias/metabolismo , Pneumopatias/patologia , Inibidores de Metaloproteinases de Matriz/síntese química , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Imagem Molecular/métodos , Sondas Moleculares/síntese química , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
11.
J Neuroinflammation ; 16(1): 133, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31266507

RESUMO

BACKGROUND: Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4+ T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng, under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. OBJECTIVE: We used a conditional mouse Oct1 (Pou2f1) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. RESULTS: Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4+ T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. CONCLUSION: Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit.


Assuntos
Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Fatores de Crescimento Neural/metabolismo , Fator 1 de Transcrição de Octâmero/deficiência , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/imunologia
12.
J Neuroinflammation ; 16(1): 158, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351476

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by both inflammatory demyelination and impaired remyelination. Studies indicate that Toll-like receptor 2 (TLR2) signaling contributes to both the inflammatory component and the defective remyelination in MS. While most MS therapeutics target adaptive immunity, we recently reported that reducing TLR2 signaling in innate immune cells by inducing TLR2 tolerance attenuates adoptively transferred experimental autoimmune encephalomyelitis. Given that previous reports suggest TLR2 signaling also inhibits myelin repair, the objective of this study was to assess how reducing TLR2 signaling through TLR2 tolerance induction affects CNS myelin repair. METHODS: Chow containing 0.2% cuprizone was fed to male and female wild-type (WT) C57BL/6 mice or TLR2-deficient (TLR2-/-) mice for 5 weeks to induce demyelination. During a 2-week remyelination period following discontinuation of cuprizone, WT mice received either low dose TLR2 ligands to induce systemic TLR2 tolerance or vehicle control (VC). Remyelination was evaluated via electron microscopy and immunohistochemical analysis of microglia and oligodendrocytes in the corpus callosum. Statistical tests included 2-way ANOVA and Mann-Whitney U analyses. RESULTS: Inducing TLR2 tolerance in WT mice during remyelination significantly enhanced myelin recovery, restoring unmyelinated axon frequency and myelin thickness to baseline levels compared to VC-treated mice. Mechanistically, enhanced remyelination in TLR2 tolerized mice was associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS+ phenotype to a non-inflammatory/pro-repair Arg1+ phenotype. This result was confirmed in vitro by inducing TLR2 tolerance in WT microglia cultures. TLR2-/- mice, without TLR2 tolerance induction, also significantly enhanced myelin recovery compared to WT mice, adding confirmation that reduced TLR2 signaling is associated with enhanced remyelination. DISCUSSION: Our results suggest that reducing TLR2 signaling in vivo by inducing TLR2 tolerance significantly enhances myelin repair. Furthermore, the enhanced remyelination resulting from TLR2 tolerance induction is associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS+ phenotype to a non-inflammatory/pro-repair Arg1+ phenotype. While deletion of TLR2 would be an impractical approach in vivo, reducing innate immune signaling through TLR2 tolerance induction may represent a novel, two-pronged approach for treating both inflammatory and myelin repair components of MS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Lipopeptídeos/uso terapêutico , Microglia/metabolismo , Oligodendroglia/metabolismo , Remielinização/fisiologia , Receptor 2 Toll-Like/metabolismo , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento
13.
EMBO J ; 38(16): e101397, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31290162

RESUMO

NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of NLR family, is a negative regulator of inflammatory signaling pathways in innate and adaptive immune cells. Previous reports have shown that NLRC3 is expressed in dendritic cells (DCs). However, the role of NLRC3 in DC activation and immunogenicity is unclear. In the present study, we find that NLRC3 attenuates the antigen-presenting function of DCs and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets. Loss of NLRC3 promotes pathogenic Th1 and Th17 responses and enhanced experimental autoimmune encephalomyelitis (EAE) development. NLRC3 negatively regulates the antigen-presenting function of DCs via p38 signaling pathway. Vaccination with NLRC3-overexpressed DCs reduces EAE progression. Our findings support that NLRC3 serves as a potential target for treating adaptive immune responses driving multiple sclerosis and other autoimmune disorders.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Animais , Apresentação do Antígeno , Autoimunidade , Linfócitos T CD4-Positivos/transplante , Polaridade Celular , Células Cultivadas , Células Dendríticas/citologia , Encefalomielite Autoimune Experimental/terapia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Transdução de Sinais , Células Th1/citologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Vacinação
14.
Med Hypotheses ; 128: 25-27, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31203904

RESUMO

Nanobacteria or calcifying nanoparticles are 80-500 nm sized nano-organisms that are physically associated with carbonate apatite mineral formations. They have been indicated in various diseases, including kidney stone formation, Alzheimer's disease, and atherosclerosis. Nanoparticles contain calcium and apatite-binding protein fetuin-A, a calcification inhibitor. However, recent evidence indicates that fetuin-A can form nucleation seeds or nidi that grow in size through ion sedimentation to become larger amorphous nanoparticles in the presence of excess calcium and apatite ions. Fetuin-A also functions as an inhibitor of meprin, a metalloproteinase implicated in inflammation and neurodegenerative diseases. During inflammation, meprin functions to regulate chemokine activity of monocyte chemotactic protein 1, which is associated with chronic inflammatory diseases, including atherosclerosis, renal inflammatory diseases, and multiple sclerosis (MS). In addition, calcium phosphate nanocrystals that contain fetuin-A are pro-inflammatory to macrophages and promote vascular smooth muscle cell mineralization, potentiating a vicious cycle of inflammation and calcification. Thus, mineral stress and inflammation appear to be associated with each other. Furthermore, fetuin-A deficient mice exhibited reduced experimental autoimmune encephalomyelitis severity. Thus, fetuin-A plays a direct role in the neuroinflammatory response. Indeed, the level of fetuin-A in cerebrospinal fluid has been defined as a biomarker of disease activity in MS. MS is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with an unknown etiology. The "inside-out" model of MS, supported by recent data, states that the initial axonal degeneration in the CNS occurs before demyelination, which then stimulates an auto-immune attack. It was shown very recently that influx of calcium from the extracellular space through nanoscale ruptures of the axonal plasma membrane predict axon degeneration in neuroinflammation. Calcium is an activator of calpains, proteases that function to break down the cytoskeleton, leading to neurodegeneration. Nanoruptures of the plasma membrane were suggested to occur at the early stages of axon damage, especially at nodes of Ranvier, which are devoid of myelin. Here, I propose that calcifying nanoparticles may have a role in the etiology and/or pathophysiology of MS. The initial event causing neurodegeneration may be due to the nanoparticles that have been suggested to easily cross the blood-brain barrier. Following this, the nanoparticles may create nanoruptures in the axonal membrane and also increase the calcium concentration around and within the neurons by forming nidi for calcification, eventually causing neurodegeneration. Nanoparticles can self-replicate; hence, they may represent an infectious causative agent for the development of MS.


Assuntos
Nanopartículas Calcificantes/efeitos adversos , Calcinose/metabolismo , Esclerose Múltipla/etiologia , Animais , Apatitas/química , Barreira Hematoencefálica/metabolismo , Nanopartículas Calcificantes/química , Cálcio/química , Sistema Nervoso Central/metabolismo , Quimiocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Inflamação , Íons , Camundongos , Esclerose Múltipla/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , alfa-2-Glicoproteína-HS/química
15.
J Neuroinflammation ; 16(1): 130, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248427

RESUMO

BACKGROUND: Multiple sclerosis (MS) involves a misdirected immune attack against myelin in the brain and spinal cord, leading to profound neuroinflammation and neurodegeneration. While the mechanisms of disease pathogenesis have been widely studied, the suppression mechanisms that lead to the resolution of the autoimmune response are still poorly understood. Here, we investigated the role of the C-type lectin receptor macrophage galactose-type lectin (MGL), usually expressed on tolerogenic antigen-presenting cells (APCs), as a negative regulator of autoimmune-driven neuroinflammation. METHODS: We used in silico, immunohistochemical, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analysis to explore the expression and functionality of MGL in human macrophages and microglia, as well as in MS post-mortem tissue. In vitro, we studied the capacity of MGL to mediate apoptosis of experimental autoimmune encephalomyelitis (EAE)-derived T cells and mouse CD4+ T cells. Finally, we evaluated in vivo and ex vivo the immunomodulatory potential of MGL in EAE. RESULTS: MGL plays a critical role in the resolution phase of EAE as MGL1-deficient (Clec10a-/-) mice showed a similar day of onset but experienced a higher clinical score to that of WT littermates. We demonstrate that the mouse ortholog MGL1 induces apoptosis of autoreactive T cells and diminishes the expression of pro-inflammatory cytokines and inflammatory autoantibodies. Moreover, we show that MGL1 but not MGL2 induces apoptosis of activated mouse CD4+ T cells in vitro. In human settings, we show that MGL expression is increased in active MS lesions and on alternatively activated microglia and macrophages which, in turn, induces the secretion of the immunoregulatory cytokine IL-10, underscoring the clinical relevance of this lectin. CONCLUSIONS: Our results show a new role of MGL-expressing APCs as an anti-inflammatory mechanism in autoimmune neuroinflammation by dampening pathogenic T and B cell responses, uncovering a novel clue for neuroprotective therapeutic strategies with relevance for in MS clinical applications.


Assuntos
Assialoglicoproteínas/biossíntese , Encefalomielite Autoimune Experimental/metabolismo , Lectinas Tipo C/biossíntese , Proteínas de Membrana/biossíntese , Microglia/metabolismo , Animais , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Ratos
16.
J Pharmacol Exp Ther ; 370(3): 437-446, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31248979

RESUMO

Multiple sclerosis is a neurodegenerative disease affecting predominantly female patients between 20 and 45 years of age. We previously reported the significant contribution of mouse mast cell protease 4 (mMCP-4) in the synthesis of endothelin-1 (ET-1) in healthy mice and in a murine model of experimental autoimmune encephalomyelitis (EAE). In the current study, the cardiovascular effects of ET-1 and big endothelin-1 (big-ET-1) administered systemically or intrathecally were assessed in the early preclinical phase of EAE in telemetry instrumented/conscious mice. Chymase-specific enzymatic activity was also measured in the lung, brain, and mast cell extracts in vitro. Finally, the impact of EAE immunization was studied on the pulmonary and brain mRNA expression of different genes of the endothelin pathway, interleukin-33 (IL-33), and monitoring of immunoreactive tumor necrosis factor-α (TNF-α). Systemically or intrathecally administered big-ET-1 triggered increases in blood pressure in conscious mice. One week post-EAE, the pressor responses to big-ET-1 were potentiated in wild-type (WT) mice but not in mMCP-4 knockout (KO) mice. EAE triggered mMCP-4-specific activity in cerebral homogenates and peritoneal mast cells. Enhanced pulmonary, but not cerebral preproendothelin-1 and IL-33 mRNA were found in KO mice and further increased 1 week post-EAE immunization, but not in WT animals. Finally, TNF-α levels were also increased in serum from mMCP-4 KO mice, but not WT, 1 week post-EAE. Our study suggests that mMCP-4 activity is enhanced both centrally and systemically in a mouse model of EAE.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Endotelina-1/administração & dosagem , Endotelina-1/farmacologia , Serina Endopeptidases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Técnicas de Inativação de Genes , Hemodinâmica/efeitos dos fármacos , Injeções Espinhais , Interleucina-33/deficiência , Interleucina-33/genética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina Endopeptidases/deficiência , Serina Endopeptidases/genética , Regulação para Cima/efeitos dos fármacos
17.
J Physiol Sci ; 69(5): 723-732, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177508

RESUMO

Our previous demonstration that severe experimental autoimmune encephalomyelitis (EAE) increases MnSOD protein abundance in the mouse kidney cortex led this study to elucidate the underlying mechanism with monensin-treated HEK293 cells as a model. Severe EAE increases mitochondrial protein abundance of SGK1 kinase and Tom20, a critical subunit of mitochondrial translocase in the renal cortex. In HEK293 cells, catalase inhibits monensin-induced increases of mitochondrial SGK1 and Tom20 protein levels. Further, GSK650394, a specific inhibitor of SGK1 reduces monensin-induced increase of mitochondrial protein abundance of Tom20 and MnSOD. Finally, RNAi of Tom20 reduces the effect of monensin on MnSOD. MnSOD and Tom20 physically associate with each other. In conclusion, in HEK293 cells, mitochondrial reactive oxygen species increase protein abundance of mitochondrial SGK1, which leads to a rise of mitochondrial Tom20, resulting in importing MnSOD protein into the mitochondria. This could be a mechanism by which severe EAE up-regulates mitochondrial MnSOD in the kidney cortex.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Córtex Renal/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Superóxido Dismutase/metabolismo , Regulação para Cima/fisiologia , Animais , Catalase/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Arthritis Rheumatol ; 71(11): 1869-1878, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31233276

RESUMO

OBJECTIVE: Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) suppresses Th17 development and ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms. METHODS: MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17-polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional-knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia-inducible factor 1α (HIF-1α) was examined by Western blotting. RESULTS: Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17-dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional-knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF-1α protein, which induces glycolysis. CONCLUSION: We demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17-related autoimmune diseases. Mechanistically, we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing HIF-1α protein in Th17 cells.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/genética , Glutaminase/antagonistas & inibidores , Glicólise/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/genética , Sulfetos/farmacologia , Tiadiazóis/farmacologia , Adulto , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Glutaminase/genética , Glutamina/efeitos dos fármacos , Glutamina/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Pessoa de Meia-Idade , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
19.
Neuroscience ; 409: 120-129, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31051217

RESUMO

Fatty acid binding protein 7 (FABP7) is expressed in astrocytes of the developing and mature central nervous system, and modulates astrocyte function by controlling intracellular fatty acid homeostasis. Astrocytes in the spinal cord have an important role in the process of myelin degeneration and regeneration. In the present study, the authors examined the role of FABP7 in astrocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE), which is an established model of multiple sclerosis (MS). FABP7 was expressed in the white matter astrocytes and increased after EAE onset; particularly strong expression was observed in demyelinating regions. In FABP7-knockout (KO) mice, the onset of EAE symptoms occurred earlier than in wild type (WT) mice, and mRNA expression levels of inflammatory cytokines (IL-17 and TNF-α) were higher in FABP7-KO lumbar spinal cord than in WT lumbar spinal cord at early stage of EAE. Interestingly, however, the clinical score was significantly reduced in FABP7-KO mice compared with WT mice in the late phase of EAE. Moreover, the area exhibiting expression of fibronectin, which is an extracellular matrix protein mainly produced by astrocytes and inhibits remyelination of oligodendrocytes, was significantly decreased in FABP7-KO compared with WT mice. Collectively, FABP7 in astrocyte may have a role to protect from the induction of inflammation leading to demyelination in CNS at early phase of EAE. Moreover, FABP7 may be involved in the regulation of fibronectin production through the modification of astrocyte activation at late phase of EAE.


Assuntos
Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Medula Espinal/metabolismo , Animais , Citocinas/metabolismo , Proteína 7 de Ligação a Ácidos Graxos/genética , Feminino , Fibronectinas/metabolismo , Camundongos , Camundongos Knockout , Bainha de Mielina/metabolismo , Substância Branca/metabolismo
20.
PLoS One ; 14(4): e0215981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31026283

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE). METHODS: An in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4+ T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG)35-55 and the adoptive transfer of encephalitogenic CD4+ T cells were used to induce EAE. RESULTS: Molecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 (Cyp1a1) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo, GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-ß (TGF-ß). Furthermore, GA reduced infiltration of CD4+CD45+ T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4+ T cells were not entirely responsible for the ameliorative effects of GA. CONCLUSION: Our findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that GA is a potential therapeutic agent to control inflammation in autoimmune diseases such as MS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Animais , Astrócitos/patologia , Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Microglia/patologia , Domínios Proteicos , Receptores de Hidrocarboneto Arílico/química
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