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1.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445295

RESUMO

Skeletal muscle is affected in experimental autoimmune encephalomyelitis (EAE), which is a model of multiple sclerosis that produces changes including muscle atrophy; histological features of neurogenic involvement, and increased oxidative stress. In this study, we aimed to evaluate the therapeutic effects of transcranial magnetic stimulation (TMS) on the involvement of rat skeletal muscle and to compare them with those produced by natalizumab (NTZ). EAE was induced by injecting myelin oligodendrocyte glycoprotein (MOG) into Dark Agouti rats. Both treatments, NTZ and TMS, were implemented from day 15 to day 35. Clinical severity was studied, and after sacrifice, the soleus and extensor digitorum longus muscles were extracted for subsequent histological and biochemical analysis. The treatment with TMS and NTZ had a beneficial effect on muscle involvement in the EAE model. There was a clinical improvement in functional motor deficits, atrophy was attenuated, neurogenic muscle lesions were reduced, and the level of oxidative stress biomarkers was lower in both treatment groups. Compared to NTZ, the best response was obtained with TMS for all the parameters analyzed. The myoprotective effect of TMS was higher than that of NTZ. Thus, the use of TMS may be an effective strategy to reduce muscle involvement in multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/terapia , Atrofia Muscular/prevenção & controle , Estimulação Magnética Transcraniana , Animais , Contagem de Células , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Glicoproteína Mielina-Oligodendrócito , Natalizumab/farmacologia , Ratos
2.
J Immunol ; 207(6): 1513-1521, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34400521

RESUMO

B cells have been implicated in the pathogenesis of multiple sclerosis, but the mechanisms that guide B cell activation in the periphery and subsequent migration to the CNS remain incompletely understood. We previously showed that systemic inflammation induces an accumulation of B cells in the spleen in a CCR6/CCL20-dependent manner. In this study, we evaluated the role of CCR6/CCL20 in the context of myelin oligodendrocyte glycoprotein (MOG) protein-induced (B cell-dependent) experimental autoimmune encephalomyelitis (EAE). We found that CCR6 is upregulated on murine B cells that migrate into the CNS during neuroinflammation. In addition, human B cells that migrate across CNS endothelium in vitro were found to be CCR6+, and we detected CCL20 production by activated CNS-derived human endothelial cells as well as a systemic increase in CCL20 protein during EAE. Although mice that lack CCR6 expression specifically on B cells exhibited an altered germinal center reaction in response to MOG protein immunization, CCR6-deficient B cells did not exhibit any competitive disadvantage in their migration to the CNS during EAE, and the clinical and pathological presentation of EAE induced by MOG protein was unaffected. These data, to our knowledge, provide new information on the role of B cell-intrinsic CCR6 expression in a B cell-dependent model of neuroinflammation.


Assuntos
Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Centro Germinativo/imunologia , Imunização/métodos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Receptores CCR6/deficiência , Animais , Linfócitos B/metabolismo , Doadores de Sangue , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Células Cultivadas , Quimiocina CCL20/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Células Endoteliais/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/genética , Receptores CCR6/genética , Proteínas Recombinantes/administração & dosagem
3.
J Neuroimmunol ; 356: 577582, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33910137

RESUMO

We explored whether experimental autoimmune encephalomyelitis (EAE) in Biozzi mice recapitulates temporal dynamics of tissue injury, immune-pathogenesis and CNS compartmentalization occurring in progressive multiple sclerosis (MS). Chronic EAE exhibited relapsing and progressing disease, partial closure of BBB, reduced tissue inflammatory activity, and development of meningeal ectopic lymphoid tissue, directly opposing (potentially driving) spinal subpial demyelinated plaques. A T cell predominant disease during relapses transformed into a B cell predominant disease in late chronic EAE, with high serum anti-MOG reactivity. Thus, late chronic Biozzi EAE recapitulates essential features of progressive MS, and is suitable for developing disease modifying and regenerative therapies.


Assuntos
Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla Crônica Progressiva/imunologia , Medula Espinal/imunologia , Animais , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Adjuvante de Freund/toxicidade , Camundongos , Camundongos Biozzi , Esclerose Múltipla Crônica Progressiva/induzido quimicamente , Esclerose Múltipla Crônica Progressiva/patologia , Medula Espinal/patologia
4.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805762

RESUMO

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX's effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.


Assuntos
Linfócitos B/patologia , Encefalomielite Autoimune Experimental/patologia , Toxina Pertussis/administração & dosagem , Células Th17/patologia , Transferência Adotiva/métodos , Animais , Linfócitos B/imunologia , Movimento Celular/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Índice de Gravidade de Doença , Células Th17/imunologia , Células Th17/transplante
5.
Molecules ; 26(7)2021 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-33916567

RESUMO

The exact mechanisms of multiple sclerosis (MS) development are still unknown, but the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice is associated with the violation of bone marrow hematopoietic stem cells (HSCs) differentiation profiles associated with the production of harmful for human's autoantibodies hydrolyzing myelin basic protein, myelin oligodendrocyte glycoprotein (MOG35-55), and DNA. It was shown that IgGs from the sera of healthy humans and autoimmune patients oxidize many different compounds due to their H2O2-dependent peroxidase and oxidoreductase activity in the absence of H2O2. Here we first analyzed the change in the relative redox activities of IgGs antibodies from the blood of C57BL/6 mice over time at different stages of the EAE development. It was shown that the peroxidase activity of mice IgGs in the oxidation of ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) is on average 6.9-fold higher than the oxidoreductase activity. The peroxidase activity of IgGs increased during the spontaneous development of EAE during 40 days, 1.4-fold. After EAE development acceleration due to mice immunization with MOG35-55 (5.3-fold), complexes of bovine DNA with methylated bovine serum albumin (DNA-metBSA; 3.5-fold), or with histones (2.6-fold), the activity was increased much faster. The increase in peroxidase activity after mice immunization with MOG35-55 and DNA-metBSA up to 40 days of experiments was relatively gradual, while for DNA-histones complex was observed its sharp increase at the acute phase of EAE (14-20 days). All data show that IgGs' redox activities can play an important role in the protection of mice from toxic compounds and oxidative stress.


Assuntos
Anticorpos Catalíticos/metabolismo , Autoanticorpos/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Células-Tronco Hematopoéticas/imunologia , Oxirredutases/metabolismo , Peroxidases/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Imunoglobulina G/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Oxirredução , Oxirredutases/imunologia , Fragmentos de Peptídeos/administração & dosagem , Peroxidases/imunologia
6.
Front Immunol ; 12: 533423, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815353

RESUMO

Voltage gated sodium (Nav) channels contribute to axonal damage following demyelination in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). The Nav1.6 isoform has been implicated as a primary contributor in this process. However, the role of Nav1.6 in immune processes, critical to the pathology of both MS and EAE, has not been extensively studied. EAE was induced with myelin oligodendrocyte (MOG35-55) peptide in Scn8admu/+ mice, which have reduced Nav1.6 levels. Scn8admu/+ mice demonstrated improved motor capacity during the recovery and early chronic phases of EAE relative to wild-type animals. In the optic nerve, myeloid cell infiltration and the effects of EAE on the axonal ultrastructure were also significantly reduced in Scn8admu/+ mice. Analysis of innate immune parameters revealed reduced plasma IL-6 levels and decreased percentages of Gr-1high/CD11b+ and Gr-1int/CD11b+ myeloid cells in the blood during the chronic phase of EAE in Scn8admu/+ mice. Elevated levels of the anti-inflammatory cytokines IL-10, IL-13, and TGF-ß1 were also observed in the brains of untreated Scn8admu/+ mice. A lipopolysaccharide (LPS) model was used to further evaluate inflammatory responses. Scn8admu/+ mice displayed reduced inflammation in response to LPS challenge. To further evaluate if this was an immune cell-intrinsic difference or the result of changes in the immune or hormonal environment, mast cells were derived from the bone marrow of Scn8admu/+ mice. These mast cells also produced lower levels of IL-6, in response to LPS, compared with those from wild type mice. Our results demonstrate that in addition to its recognized impact on axonal damage, Nav1.6 impacts multiple aspects of the innate inflammatory response.


Assuntos
Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Inflamação/genética , Esclerose Múltipla/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Animais , Axônios/metabolismo , Encéfalo/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Expressão Gênica , Heterozigoto , Humanos , Inflamação/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
ACS Biomater Sci Eng ; 7(3): 1242-1251, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33586954

RESUMO

Multiple sclerosis (MS) is a demyelinating chronic autoimmune inflammatory disease of the central nervous system (CNS). A large amount of proinflammatory cytokines is released in the CNS from the self-reactive T cells infiltrate, leading to the destruction of the myelin sheath and contributing to the development of MS. Several drugs have emerged in recent years to treat MS, and studies have shown that gold nanoparticles (GNPs) have anti-inflammatory properties in autoimmune diseases. Thus, the effects of GNP conjugation to ethylene dicysteine diethyl ester (ECD) were evaluated in C57BL/6 female mice exposed to experimental MS. Animals were exposed to experimental autoimmune encephalitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The clinical and cerebral effects of the different doses of ECD-GNPs (0.3, 0.6, and 1.0 mg/kg) were first studied, and the results showed that the group treated with 0.6 mg/kg ECD-GNPs improved clinical symptoms, inflammatory infiltrate, and myelin integrity. In the following step, GNPs and ECD-GNPs (0.6 mg/kg) showed improvements in the clinical signs of the disease. Moreover, there was a reduction in the levels of proinflammatory cytokines in both groups compared to EAE, and only the isolated use of GNPs increased IL-4 expression. Both NF-κB and TGFß immunoexpression were significantly reduced following EAE + GNPs and EAE + ECD-GNPs treatment. In conclusion, GNPs and ECD-GNPs at 0.6 mg/kg attenuate the neurological signs of EAE likely due to inhibition of neuroinflammation induced by EAE.


Assuntos
Encefalomielite Autoimune Experimental , Nanopartículas Metálicas , Animais , Cisteína/análogos & derivados , Encefalomielite Autoimune Experimental/induzido quimicamente , Ésteres , Feminino , Ouro , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL
8.
Exp Neurol ; 335: 113488, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32991933

RESUMO

BACKGROUND: The human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion. OBJECTIVES: We investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology. METHODS: C57Bl/6, 8-week old mice were immunized with 200 huMOG1-125 and treated with 50 µg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test. RESULTS: Anti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001). CONCLUSIONS: Anti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.


Assuntos
Anticorpos/uso terapêutico , Antígenos CD20/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Substância Cinzenta/patologia , Glicoproteína Mielina-Oligodendrócito , Animais , Atrofia , Linfócitos B/imunologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Macrófagos/imunologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos
9.
Int Immunopharmacol ; 91: 107278, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341737

RESUMO

While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis.


Assuntos
Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/prevenção & controle , Ácido Mevalônico/metabolismo , Quinolinas/farmacologia , Medula Espinal/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Medula Espinal/imunologia , Medula Espinal/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
10.
Int Immunopharmacol ; 88: 106998, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33182064

RESUMO

Multiple sclerosis (MS) is an autoimmune disease for which conventional treatments have limited efficacy or side effects. Free radicals are primarily involved in blood-brain barrier disruption and induce neuronal and axonal damage, thus promoting the development of MS. Amifostine, a radioprotective drug used as a cytoprotective agent, attenuates oxidative stress and improves radiation damage by acting as a direct scavenger of reactive oxygen and nitrogen species. The aim of this study was to evaluate the effects of amifostine on MS in a mouse model of experimental autoimmune encephalomyelitis (EAE), which was developed by immunizing C57BL/6 mice with myelin oligodendrocyte glycoprotein and pertussis toxin. EAE mice received intraperitoneal injections of amifostine prior to onset of clinical symptoms and were monitored up to day 15 post induction. We observed abnormal clinical behavioral scores and a decrease in body weight. Histological analysis showed severe inflammatory infiltration and demyelination in the brain and spinal cord lumbar enlargements where significant upregulation of the mRNA expression of the pro-inflammatory cytokines interleukin-6 and interleukin-8, downregulation of the anti-inflammatory cytokine interleukin-10, and obvious microgliosis were also observed. Amifostine treatment potently reversed these abnormal changes. The anti-inflammatory effect of amifostine was associated with the inhibition of reactive oxygen species generation. Furthermore, the expression of proteins involved in the NLRP3 signaling pathway and pyroptosis was decreased. In conclusion, our study showed that amifostine ameliorates induction of experimental autoimmune encephalomyelitis via anti-inflammatory and anti-pyroptosis effects, providing further insights into the use of amifostine for the treatment of MS.


Assuntos
Amifostina/uso terapêutico , Encefalomielite Autoimune Experimental/induzido quimicamente , Esclerose Múltipla/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fragmentos de Peptídeos/toxicidade , Protetores contra Radiação/uso terapêutico , Espécies Reativas de Oxigênio
11.
Front Immunol ; 11: 1883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983109

RESUMO

Cluster of differentiation 226 (CD226) molecules play a crucial role in the activation of effector CD4+ T cells during the immune response process, but a cell-intrinsic function of CD226 in CD4+ T subsets is not clear. In this study, we showed that Cd226 -/- mice were resistant to myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) with highly expressed IL-10+CD4+ T cells and downregulated IL-17A+CD4+ T cells when compared with wild-type (WT) mice. Th17 cell infiltration into the central nervous system (CNS) was largely decreased in the absence of CD226 during EAE. CD226 deficiency facilitated the proliferation of regulatory T cells (Tregs), with increased numbers of Tregs observed in EAE mice, and supported the elevated induced regulatory T cell (iTregs) proliferation in vitro. The Akt and Erk signaling pathways were shown to be involved in Cd226 -/- Treg proliferation and function in vivo and in vitro. These findings collectively indicate that CD226 is a key molecule regulating the Treg-mediated suppression of autoimmune responses by inhibiting Treg proliferation. Thus, the results of this study identify additional mechanisms by which CD226 regulates Treg functions in EAE and supports the potential therapeutic effects of anti-CD226 molecules on autoimmune diseases.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Proliferação de Células , Sistema Nervoso Central/enzimologia , Encefalomielite Autoimune Experimental/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ativação Linfocitária , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T Reguladores/enzimologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Células Cultivadas , Sistema Nervoso Central/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th17/metabolismo
12.
APMIS ; 128(11): 583-592, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32865844

RESUMO

Multiple sclerosis (MS) is an immune-mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)-induced mice were explored. Thirty-two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 µg, and 50ng + 125 µg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T-bet, IFN-γ, GATA-3, and IL-4 genes expression were assessed in the splenocytes of EAE -induced mice. The expression of T-bet and IFN-γ genes in the splenocytes of ATRA, calcitriol and combination- treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T-bet expression was observed in the combination-treated group compared to the ATRA-treated group (p < 0.05). The expression of GATA3 and IL-4 genes was significantly increased in the ATRA-, calcitriol-, and combination-treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.


Assuntos
Calcitriol/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Esquema de Medicação , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
13.
Microbiol Immunol ; 64(8): 563-569, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32401403

RESUMO

The present study was to demonstrate that the G protein coupled receptors serve as targets for the treatment of autoimmune disease such as rheumatoid arthritis and multiple sclerosis. Rats received pristane at the base of the tail. Affected joints were counted daily. The T cell mediated autoimmune diseases such as pristine-induced arthritis (PIA) and autoimmune encephalomyelitis (EAE) in a rat model were profoundly ameliorated by treatment with the specific G protein couple receptors 120 (GPR120) stimuli omega-3 fatty acids (ω-3 FAs). Our study further revealed that the activation of GPR120 by ω-3 FAs can result in a decrease of phosphorylated transforming growth factor-ß activated kinase 1 (TAK1), and further inhibit the downstream IKKß/I-κB pathway and the terminal NF-κB activation which serves as a mediator of T cell activation. ω-3 Fatty acids exhibited an inhibitory effect on TAK1 by enhancing the association of ß-arrestin2 and TAK1 binding protein 1 (TAB1), thus the disassociation of TAB1 from the TAB1/TAK1 complex renders a limited effect on ß-arrestin2 signaling as an innate immunity regulation. GPR120 is a functional receptor of ω-3 fatty acids in T cell-mediated autoimmune disease compared with its effect on innate immunity.


Assuntos
Artrite Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T/imunologia , Animais , Artrite Experimental/induzido quimicamente , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Quinase I-kappa B/metabolismo , Ativação Linfocitária , MAP Quinase Quinase Quinases/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Terpenos
14.
Biochem Pharmacol ; 177: 114000, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32353424

RESUMO

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 µM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood-brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/química , Alcaloides/metabolismo , Animais , Benzodioxóis/química , Benzodioxóis/metabolismo , Produtos Biológicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Cristalografia por Raios X , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Modelos Moleculares , Terapia de Alvo Molecular , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Fragmentos de Peptídeos/toxicidade , Piperidinas/química , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/metabolismo , Baço/citologia
15.
Immunity ; 52(4): 650-667.e10, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32294406

RESUMO

Appropriate balance of T helper 17 (Th17) and regulatory T (Treg) cells maintains immune tolerance and host defense. Disruption of Th17-Treg cell balance is implicated in a number of immune-mediated diseases, many of which display dysregulation of the insulin-like growth factor (IGF) system. Here, we show that, among effector T cell subsets, Th17 and Treg cells selectively expressed multiple components of the IGF system. Signaling through IGF receptor (IGF1R) activated the protein kinase B-mammalian target of rapamycin (AKT-mTOR) pathway, increased aerobic glycolysis, favored Th17 cell differentiation over that of Treg cells, and promoted a heightened pro-inflammatory gene expression signature. Group 3 innate lymphoid cells (ILC3s), but not ILC1s or ILC2s, were similarly responsive to IGF signaling. Mice with deficiency of IGF1R targeted to T cells failed to fully develop disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Thus, the IGF system represents a previously unappreciated pathway by which type 3 immunity is modulated and immune-mediated pathogenesis controlled.


Assuntos
Autoimunidade , Encefalomielite Autoimune Experimental/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptor IGF Tipo 1/imunologia , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/imunologia , Células Th17/imunologia , Animais , Comunicação Celular , Diferenciação Celular , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica , Tolerância Imunológica , Imunidade Inata , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Receptor IGF Tipo 1/genética , Transdução de Sinais , Linfócitos T Reguladores/patologia , Serina-Treonina Quinases TOR/genética , Células Th17/patologia
16.
Bull Exp Biol Med ; 168(6): 761-766, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32328934

RESUMO

We studied activities of antioxidant system enzymes in tissues of rats with experimental allergic encephalomyelitis. It was shown that the development of pathology is accompanied by deformation of the neurons and axonal degeneration, intensification of free radical oxidation, exhaustion of the reduced glutathione pool, and multidirectional changes in activities of antioxidant enzymes in rat tissues. The observed imbalance in the antioxidant defense system can be associated with excessive glutathione utilization in the glutathione transferase reaction and different severity of the pathological process in the brain and spinal cord. The received data necessitate the search for compounds that can prevent inhibition of antioxidant system components in order to analyze the possibility of their use in the treatment of multiple sclerosis.


Assuntos
Antioxidantes/metabolismo , Córtex Cerebelar/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Bulbo/metabolismo , Neurônios/metabolismo , Medula Espinal/metabolismo , Aconitato Hidratase/metabolismo , Animais , Catalase/metabolismo , Córtex Cerebelar/patologia , Ácido Cítrico/metabolismo , Misturas Complexas/administração & dosagem , Misturas Complexas/isolamento & purificação , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Masculino , Bulbo/patologia , Neurônios/patologia , Oxirredução , Estresse Oxidativo , Ratos , Ratos Wistar , Medula Espinal/química , Medula Espinal/patologia , Superóxido Dismutase/metabolismo
17.
Biomed Pharmacother ; 125: 109528, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32106388

RESUMO

Multiple sclerosis (MS) is known as an autoimmune disease in the central nervous system (CNS) characterized by motor deficits, pain, fatigue, cognitive impairment, and sensory and visual dysfunction. MS is considered to be resulted from significant inflammatory response. Paricalcitol (Pari) is a vitamin D2 analogue, which has been indicated to show anti-inflammatory activities in kidney and heart diseases. In the present study, if Pari could ameliorate the experimental autoimmune encephalomyelitis (EAE) was investigated. Here, the C57BL/6 mice were immunized using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). Subsequently, Pari was intraperitoneally injected into the mice. As for in vitro analysis, RAW264.7 and Jurkat cells were incubated with Pari together with corresponding stimulus. The results indicated that Pari administration reduced the paralytic severity, neuropathology and apoptosis in MOG-treated mice compared to the MOG single group. Pari also exhibited a significantly inhibitory effect on immune cell infiltration, glial cell activation, expression of pro-inflammatory factors and the activation of nuclear factor κB (NF-κB). The expression of pro-inflammatory regulators and the translocation of NF-κB from cytoplasm into nuclear in RAW264.7 and Jurkat cells under specific stimulation was clearly down-regulated by Pari incubation. Furthermore, we found that suppressing NF-κB with its inhibitor combined with Pari could further reduce the expression of pro-inflammatory factors and associated proteins. These data illustrated that Pari could diminish MOG-triggered EAE, as well as macrophages and T cells activation through blocking NF-κB activation. Collectively, Pari might have therapeutic effects in mouse models with MS.


Assuntos
Anti-Inflamatórios/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ergocalciferóis/farmacologia , Inflamação/metabolismo , NF-kappa B/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Células Jurkat/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Fragmentos de Peptídeos/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Cultura Primária de Células , Células RAW 264.7 , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia
18.
J Neuroinflammation ; 17(1): 68, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075650

RESUMO

BACKGROUND: CD8+ T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8+ T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. Here, we examined the role of c-Met-expressing CD8+ T cells by using a MOG35-55 T cell-mediated EAE model. METHODS: Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55 in complete Freund's adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, and c-Met expression by CD8 was evaluated by flow cytometry and immunofluorescence. Molecular, cellular, and killing function analysis were performed by real-time PCR, ELISA, flow cytometry, and killing assay. RESULTS: In the present study, we observed that a fraction of murine effector CD8+ T cells expressed c-Met receptor (c-Met+CD8+) in an experimental autoimmune encephalitis (EAE) model. Phenotypic and functional analysis of c-Met+CD8+ T cells revealed that they recognize the encephalitogenic epitope myelin oligodendrocyte glycoprotein37-50. We demonstrated that this T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of c-Met+CD8+ T cells in cell-mediated cytotoxicity reactions CONCLUSIONS: Altogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8+ T cell-mediated neuroinflammation.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Receptores Proteína Tirosina Quinases/biossíntese , Sequência de Aminoácidos , Animais , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Feminino , Adjuvante de Freund/toxicidade , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/genética , Glicoproteína Mielina-Oligodendrócito/toxicidade , Receptores Proteína Tirosina Quinases/genética
19.
J Neurochem ; 153(6): 693-709, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32031240

RESUMO

Autoimmune optic neuritis (AON), a model of multiple sclerosis-associated optic neuritis, is accompanied by degeneration of retinal ganglion cells (RGCs) and optic nerve demyelination and axonal loss. In order to investigate the role of N-methyl-d-aspartate (NMDA) receptors in mediating RGC degeneration, upstream changes in the optic nerve actin cytoskeleton and associated deterioration in visual function, we induced AON in Brown Norway rats by immunization with myelin oligodendrocyte glycoprotein. Subsequently, visual acuity was assessed by recording visual evoked potentials and electroretinograms prior to extraction of optic nerves for western blot analysis and retinas for quantification of RGCs. As previously reported, in Brown Norway rats RGC degeneration is observed prior to onset of immune cell infiltration and demyelination of the optic nerves. However, within the optic nerve, destabilization of the actin cytoskeleton could be seen as indicated by an increase in the globular to filamentous actin ratio. Interestingly, these changes could be mimicked by intravitreal injection of glutamate, and similarly blocked by application of the NMDA receptor blocker MK-801, leading us to propose that prior to optic nerve lesion formation, NMDA receptor activation within the retina leads to retinal calcium accumulation, actin destabilization within the optic nerve as well as a deterioration of visual acuity during AON.


Assuntos
Neurite Óptica/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Animais , Maleato de Dizocilpina/farmacologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Potenciais Evocados Visuais/efeitos dos fármacos , Potenciais Evocados Visuais/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Glicoproteína Mielina-Oligodendrócito/toxicidade , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/imunologia , Nervo Óptico/metabolismo , Neurite Óptica/induzido quimicamente , Neurite Óptica/imunologia , Ratos , Ratos Endogâmicos BN , Receptores de N-Metil-D-Aspartato/imunologia , Retina/efeitos dos fármacos , Retina/imunologia
20.
J Neuroimmune Pharmacol ; 15(2): 249-263, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31828731

RESUMO

The renin angiotensin system (RAS), which is classically known for blood pressure regulation, has functions beyond this. There are two axes of RAS that work to counterbalance each other and are active throughout the body, including the CNS. The pathological axis, consisting of angiotensin II (A1-8), angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R), is upregulated in many CNS diseases, including multiple sclerosis (MS). MS is an autoimmune and neurodegenerative disease of the CNS characterized by inflammation, demyelination and axonal degeneration. Published research has described increased expression of AT1R and ACE in tissues from MS patients and in animal models of MS such as experimental autoimmune encephalomyelitis (EAE). In contrast to the pathological axis, little is known about the protective axes of RAS in MS and EAE. In other neurological conditions the protective axis, which includes A1-7, ACE2, angiotensin II type 2 receptor and Mas receptor, has been shown to have anti-inflammatory, regenerative and neuroprotective effects. Here we show, for the first time, changes in the protective arm of RAS in both EAE and MS CNS tissue. We observed a significant increase in expression of the protective arm during stages of disease stabilization in EAE, and in MS tissue showing evidence of remyelination. These data provide evidence that the protective arm of RAS, through both ligand and receptor expression, is associated with reductions in the pathological processes that occur in the earlier stages of MS and EAE, possibly slowing the neurodegenerative process and enhancing neural repair. Graphical Abstract.


Assuntos
Encéfalo/metabolismo , Doenças Desmielinizantes/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Sistema Renina-Angiotensina/fisiologia , Medula Espinal/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células Cultivadas , Doenças Desmielinizantes/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/toxicidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia
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