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1.
Proc Natl Acad Sci U S A ; 120(4): e2216941120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36669102

RESUMO

In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. ß-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.


Assuntos
Histonas , Propionatos , Humanos , Propionatos/farmacologia , Histonas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neuroproteção , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Gânglios Espinais/metabolismo
2.
Immunity ; 43(4): 817-29, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26488817

RESUMO

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.


Assuntos
Autoimunidade/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Gorduras na Dieta/farmacologia , Duodeno/imunologia , Encefalomielite Autoimune Experimental/etiologia , Ácidos Graxos/farmacologia , Linfopoese/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Animais , Gorduras na Dieta/toxicidade , Duodeno/metabolismo , Duodeno/microbiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Ácidos Graxos/química , Ácidos Graxos/toxicidade , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiologia , Regulação da Expressão Gênica/imunologia , Ácidos Láuricos/toxicidade , Receptores X do Fígado , Sistema de Sinalização das MAP Quinases , Camundongos , Peso Molecular , Receptores Nucleares Órfãos/biossíntese , Receptores Nucleares Órfãos/genética , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/genética , Baço/imunologia , Baço/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Transcriptoma
3.
J Neuroinflammation ; 17(1): 9, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915017

RESUMO

BACKGROUND: The multi-drug resistance transporter ABCG2, a member of the ATP-binding cassette (ABC) transporter family, mediates the efflux of different immunotherapeutics used in multiple sclerosis (MS), e.g., teriflunomide (teri), cladribine, and mitoxantrone, across cell membranes and organelles. Hence, the modulation of ABCG2 activity could have potential therapeutic implications in MS. In this study, we aimed at investigating the functional impact of abcg2 modulation on teri-induced effects in vitro and in vivo. METHODS: T cells from C57BL/6 J wild-type (wt) and abcg2-knockout (KO) mice were treated with teri at different concentrations with/without specific abcg2-inhibitors (Ko143; Fumitremorgin C) and analyzed for intracellular teri concentration (HPLC; LS-MS/MS), T cell apoptosis (annexin V/PI), and proliferation (CSFE). Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J by active immunization with MOG35-55/CFA. Teri (10 mg/kg body weight) was given orally once daily after individual disease onset. abcg2-mRNA expression (spinal cord, splenic T cells) was analyzed using qRT-PCR. RESULTS: In vitro, intracellular teri concentration in T cells was 2.5-fold higher in abcg2-KO mice than in wt mice. Teri-induced inhibition of T cell proliferation was two fold increased in abcg2-KO cells compared to wt cells. T cell apoptosis demonstrated analogous results with 3.1-fold increased apoptosis after pharmacological abcg2-inhibition in wt cells. abcg2-mRNA was differentially regulated during different phases of EAE within the central nervous system and peripheral organs. In vivo, at a dosage not efficacious in wt animals, teri treatment ameliorated clinical EAE in abcg2-KO mice which was accompanied by higher spinal cord tissue concentrations of teri. CONCLUSION: Functional relevance of abcg2 modulation on teri effects in vitro and in vivo warrants further investigation as a potential determinant of interindividual treatment response in MS, with potential implications for other immunotherapies.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/fisiologia , Crotonatos/uso terapêutico , Modelos Animais de Doenças , Imunoterapia/métodos , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Toluidinas/uso terapêutico , Animais , Crotonatos/farmacologia , Feminino , Humanos , Hidroxibutiratos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Nitrilas , Ratos , Linfócitos T/efeitos dos fármacos , Toluidinas/farmacologia
5.
Acta Neuropathol ; 138(3): 443-456, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31030237

RESUMO

The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35-55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8+ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8+ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy.


Assuntos
Calcitriol/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Glucocorticoides/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Encefalomielite Autoimune Experimental/imunologia , Humanos , Camundongos , Esclerose Múltipla , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/fisiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
6.
Sci Rep ; 14(1): 17823, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090252

RESUMO

So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35-55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.


Assuntos
Azetidinas , Compostos de Benzil , Fator Neurotrófico Derivado do Encéfalo , Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Feminino , Camundongos , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Compostos de Benzil/farmacologia , Compostos de Benzil/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia
7.
Cells ; 12(4)2023 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-36831209

RESUMO

Background: Glatiramer acetate (GA) is a well-established treatment option for patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS) with few side effects. The double transgenic mouse model spontaneous opticospinal encephalomyelitis (OSE), based on recombinant myelin oligodendrocyte glycoprotein35-55 reactive T and B cells, mimicks features of chronic inflammation and degeneration in MS and related disorders. Here, we investigated the effects of prophylactic GA treatment on the clinical course, histological alterations and peripheral immune cells in OSE. Objective: To investigate the effects of prophylactic glatiramer acetate (GA) treatment in a mouse model of spontaneous opticospinal encephalomyelitis (OSE). Methods: OSE mice with a postnatal age of 21 to 28 days without signs of encephalomyelitis were treated once daily either with 150 µg GA or vehicle intraperitoneally (i. p.). The animals were scored daily regarding clinical signs and weight. The animals were sacrificed after 30 days of treatment or after having reached a score of 7.0 due to animal care guidelines. We performed immunohistochemistry of spinal cord sections and flow cytometry analysis of immune cells. Results: Preventive treatment with 150 µg GA i. p. once daily significantly reduced clinical disease progression with a mean score of 3.9 ± 1.0 compared to 6.2 ± 0.7 in control animals (p < 0.01) after 30 d in accordance with positive effects on weight (p < 0.001). The immunohistochemistry showed that general inflammation, demyelination or CD11c+ dendritic cell infiltration did not differ. There was, however, a modest reduction of the Iba1+ area (p < 0.05) and F4/80+ area upon GA treatment (p < 0.05). The immune cell composition of secondary lymphoid organs showed a trend towards an upregulation of regulatory T cells, which lacked significance. Conclusions: Preventive treatment with GA reduces disease progression in OSE in line with modest effects on microglia/macrophages. Due to the lack of established prophylactic treatment options for chronic autoimmune diseases with a high risk of disability, our study could provide valuable indications for translational medicine.


Assuntos
Encefalomielite Autoimune Experimental , Encefalomielite , Camundongos , Animais , Acetato de Glatiramer/uso terapêutico , Encefalomielite Autoimune Experimental/patologia , Peptídeos/farmacologia , Inflamação/tratamento farmacológico , Camundongos Transgênicos , Encefalomielite/tratamento farmacológico , Progressão da Doença
8.
Brain ; 133(Pt 8): 2248-63, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20826430

RESUMO

Brain-derived neurotrophic factor plays a key role in neuronal and axonal survival. Brain-derived neurotrophic factor is expressed in the immune cells in lesions of experimental autoimmune encephalomyelitis and multiple sclerosis, thus potentially mediating neuroprotective effects. We investigated the functional role of brain-derived neurotrophic factor in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Mice deficient for brain-derived neurotrophic factor in immune cells displayed an attenuated immune response in the acute phase of experimental autoimmune encephalomyelitis, but progressive disability with enhanced axonal loss in the chronic phase of the disease. In mice deficient for central nervous system-derived brain-derived neurotrophic factor via glial fibrillary acidic protein-crescentin-mediated deletion, a more severe course of experimental autoimmune encephalomyelitis and an overall increased axonal loss was observed. In a lentiviral approach, injection of brain-derived neurotrophic factor-overexpressing T cells led to a less severe course of experimental autoimmune encephalomyelitis and direct axonal protection. Our data imply a functional role of brain-derived neurotrophic factor in autoimmune demyelination by mediating axon protection.


Assuntos
Autoimunidade/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Doença Aguda , Animais , Axônios/imunologia , Axônios/patologia , Encéfalo/imunologia , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/deficiência , Fator Neurotrófico Derivado do Encéfalo/genética , Doença Crônica , Avaliação da Deficiência , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Esclerose Múltipla , Neuroimunomodulação/fisiologia , Receptor trkB/metabolismo , Medula Espinal/imunologia , Medula Espinal/patologia , Linfócitos T/metabolismo
9.
J Neuroimmunol ; 328: 78-85, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30623801

RESUMO

The murine anti-CD52 antibody, an equivalent of the humanized antibody alemtuzumab, which is successfully used in the treatment of multiple sclerosis, was used to explore a potential neuroprotective effect driven by immune cell derived brain-derived neurotrophic factor (BDNF). Therefore, lineage specific constitutive knock-out mice with a BDNF deficiency in T cells and macrophages were used and compared to treated wildtype mice. Neither therapeutic nor preventive application of the murine anti-CD52 antibody in an animal model of multiple sclerosis, the MOG35-55 EAE, revealed a beneficial contribution of immune cell derived BDNF to the disease outcome. Furthermore, preventive application of the murine anti-CD52 antibody worsened the clinical EAE disease course and could only be overcome by a prolonged recovery phase after treatment and before disease induction.


Assuntos
Alemtuzumab/farmacologia , Fator Neurotrófico Derivado do Encéfalo/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fatores Imunológicos/farmacologia , Animais , Encefalomielite Autoimune Experimental/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos Neuroprotetores/farmacologia , Medula Espinal/imunologia , Medula Espinal/patologia , Linfócitos T/imunologia
10.
Brain Res ; 1636: 172-182, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26872595

RESUMO

The neuropathology of schizophrenia has been reported to be closely associated with microglial activation. In a previous study, using the prenatal PolyI:C schizophrenia animal model, we showed an increase in cell numbers and a reduction in microglial branching in 30-day-old PolyI:C descendants, which suggests that there is microglial activation during adolescence. To provide more information about the activation state, we aimed to examine the expression levels of Iba1, which was reported to be up-regulated in activated microglia. We used a flow cytometric approach and investigated CD11b and CD45, two additional markers for the identification of microglial cells. We demonstrated that intracellular staining against Iba1 can be used as a reliable flow cytometric method for identification of microglial cells. Prenatal PolyI:C treatment had long-term effects on CD11b and CD45 expression. It also resulted in a trend towards increased Iba1 expression. Imbalance in CD11b, CD45, and Iba1 expression might contribute to impaired synaptic surveillance and enhanced activation/inflammatory activity of microglia in adult offspring.


Assuntos
Citometria de Fluxo/métodos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Indutores de Interferon/toxicidade , Microglia/patologia , Poli I-C/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Antígenos Comuns de Leucócito/metabolismo , Masculino , Camundongos , Proteínas dos Microfilamentos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Caracteres Sexuais
11.
J Neuroimmunol ; 285: 16-21, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26198914

RESUMO

In this study we examined the role of fumaric acid esters (FAE) in a spontaneous and chronic animal model, the opticospinal EAE (OSE). Preventive treatment of dimethylfumarate (DMF) promotes onset of disease in animals treated with high dose DMF. This group also exhibited a significantly exacerbated disease course in a therapeutic treatment as compared to the low dose DMF approach, where less demyelination, macrophage infiltration, and increased Nrf2 expression in the spinal cord were observed. We conclude that low dose DMF treatment is effective in the therapy of the spontaneous opticospinal EAE model and mediates neuroprotective effects via the oxidative stress response pathway.


Assuntos
Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Fumaratos/administração & dosagem , Animais , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/imunologia , Ésteres , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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