RESUMO
Experimental autoimmune encephalomyelitis (EAE) induced in inbred rodents, i.e., genetically identical animals kept under identical environmental conditions, shows variable clinical outcomes. We investigated such variations of EAE in Dark Agouti rats immunized with spinal cord homogenate and identified four groups: lethal, severe, moderate, and mild, at day 28 post immunization. Higher numbers of CD4+ T cells, helper T cells type 1 (Th1) and 17 (Th17) in particular, were detected in the spinal cord of the severe group in comparison with the moderate group. In addition, increased proportion of Th1 and Th17 cells, and heightened levels of interferon (IFN)-γ and interleukin (IL)-6 were detected in the small intestine lamina propria of the severe group. A selective agonist of free fatty acid receptor type 2 (Ffar2) applied orally in the inductive phase of EAE shifted the distribution of the disease outcomes towards milder forms. This effect was paralleled with potentiation of intestinal innate lymphoid cells type 3 (ILC3) regulatory properties, and diminished Th1 and Th17 cell response in the lymph nodes draining the site of immunization. Our results suggest that different clinical outcomes in DA rats are under determinative influence of intestinal ILC3 activity during the inductive phase of EAE.
Assuntos
Encefalomielite Autoimune Experimental , Ratos , Animais , Camundongos , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/prevenção & controle , Imunidade Inata , Medula Espinal/patologia , Microglia , Células Th17 , Células Th1 , Camundongos Endogâmicos C57BLRESUMO
In the search for novel potent immunomodulatory nuclear factor-erythroid 2 related factor 2 (Nrf2) activators, a derivative of cholic bile acid, SB140, was synthesized. The synthesis of SB140 aimed to increase the electrophilic functionality of the compound, enhancing its ability to activate Nrf2. Effects of SB140 on microglial cells, myeloid-derived cells (MDC), and T cells were explored in the context of (central nervous system) CNS autoimmunity. SB140 potently activated Nrf2 signaling in MDC and microglia. It was efficient in reducing the ability of microglial cells to produce inflammatory nitric oxide, interleukin (IL)-6, and tumor necrosis factor (TNF). Also, SB140 reduced the proliferation of encephalitogenic T cells and the production of their effector cytokines: IL-17 and interferon (IFN)-γ. On the contrary, the effects of SB140 on anti-inflammatory IL-10 production in microglial and encephalitogenic T cells were limited or absent. These results show that SB140 is a potent Nrf2 activator, as well as an immunomodulatory compound. Thus, further research on the application of SB140 in the treatment of neuroinflammatory diseases is warranted. Animal models of multiple sclerosis and other inflammatory neurological disorders will be a suitable choice for such studies.
Assuntos
Anti-Inflamatórios , Ácidos e Sais Biliares , Microglia , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Ácidos e Sais Biliares/farmacologia , Ácidos e Sais Biliares/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Citocinas/metabolismo , Humanos , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Ethyl pyruvate (EP) is a redox-active compound that has been previously shown to be effective in restraining immune hyperactivity in animal models of various autoimmune and chronic inflammatory diseases. Importantly, EP has also been proven to have a potent tolerogenic effect on dendritic cells (DCs). Here, the influence of EP on the signaling pathways in DCs relevant for their tolerogenicity, including anti-inflammatory NRF2 and pro-inflammatory NF-κB, was explored. Specifically, the effects of EP on DCs obtained by GM-CSF-directed differentiation of murine bone marrow precursor cells and matured under the influence of lipopolysaccharide (LPS) were examined via immunocytochemistry and RT-PCR. EP counteracted LPS-imposed morphological changes and down-regulated the LPS-induced expression of pro-inflammatory mediators in DCs. While it reduced the activation of NF-κB, EP potentiated NRF2 and downstream antioxidative molecules, thus implying the regulation of NRF2 signaling pathways as the major reason for the tolerizing effects of EP on DCs.
Assuntos
Células Dendríticas , Lipopolissacarídeos , Fator 2 Relacionado a NF-E2 , NF-kappa B , Piruvatos , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/imunologia , Piruvatos/farmacologia , Animais , Camundongos , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Tolerância Imunológica/efeitos dos fármacos , Células CultivadasRESUMO
Gallic acid is a phenolic acid present in various plants, nuts, and fruits. It is well known for its anti-oxidative and anti-inflammatory properties. The phenethyl ester of gallic acid (PEGA) was synthesized with the aim of increasing the bioavailability of gallic acid, and thus its pharmacological potential. Here, the effects of PEGA on encephalitogenic cells were examined, and PEGA was found to modulate the inflammatory activities of T cells and macrophages/microglia. Specifically, PEGA reduced the release of interleukin (IL)-17 and interferon (IFN)-γ from T cells, as well as NO, and IL-6 from macrophages/microglia. Importantly, PEGA ameliorated experimental autoimmune encephalomyelitis, an animal model of chronic inflammatory disease of the central nervous system (CNS)-multiple sclerosis. Thus, PEGA is a potent anti-inflammatory compound with a perspective to be further explored in the context of CNS autoimmunity and other chronic inflammatory disorders.
Assuntos
Encefalomielite Autoimune Experimental , Animais , Camundongos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Sistema Nervoso Central , Microglia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
We have recently characterized experimental autoimmune encephalomyelitis (EAE) induced in DA rats with spinal cord homogenate without complete Freund's adjuvant (CFA). The main advantage of this multiple sclerosis model is the lack of CFA-related confounding effects which represent the major obstacles in translating findings from EAE to multiple sclerosis. Here, antigen specificity of the cellular and humoral immune response directed against the central nervous system was explored. The reactivity of T and B cells to myelin basic protein, myelin oligodendrocyte glycoprotein, and ß-synuclein was detected. Having in mind that reactivity against ß-synuclein was previously associated with autoimmunity against the brain, the infiltration of immune cells into different brain compartments, i.e. pons, cerebellum, hippocampus, and cortex was determined. T cell infiltration was observed in all structures examined. This finding stimulated investigation of the effects of immunization on DA rat behavior using the elevated plus maze and the open field test. Rats recovered from EAE displayed increased anxiety-like behavior. These data support CFA-free EAE in DA rats as a useful model for multiple sclerosis research.
Assuntos
Encefalomielite Autoimune Experimental , Medula Espinal , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/metabolismo , Ratos , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Modelos Animais de Doenças , Glicoproteína Mielina-Oligodendrócito/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Esclerose Múltipla/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteína Básica da Mielina/imunologia , Proteína Básica da Mielina/metabolismo , Encéfalo/patologia , Encéfalo/imunologia , Encéfalo/metabolismo , Feminino , Encefalite/imunologia , Encefalite/etiologia , Encefalite/patologia , Encefalite/metabolismo , Adjuvante de Freund/imunologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/patologiaRESUMO
Acute respiratory distress syndrome (ARDS) became a focus of intensive research due to its death toll during the Covid-19 pandemic. An uncontrolled and excessive inflammatory response mediated by proinflammatory molecules such as high mobility group box protein 1 (HMGB1), IL-6, and TNF mounts as a response to infection. In this study, ethyl pyruvate (EP), a known inhibitor of HMGB1, was tested in the model of murine ARDS induced in C57BL/6 mice by intranasal administration of polyinosinic:polycytidylic acid (poly(I:C)). Intraperitoneal administration of EP ameliorated the ARDS-related histopathological changes in the lungs of poly(I:C)-induced ARDS and decreased numbers of immune cells in the lungs, broncho-alveolar lavage fluid and draining lymph nodes (DLN). Specifically, fewer CD8+ T cells and less activated CD4+ T cells were observed in DLN. Consequently, the lungs of EP-treated animals had fewer damage-inflicting CD8+ cells and macrophages. Additionally, the expression and production of proinflammatory cytokines, IL-17, IFN-γ and IL-6 were downregulated in the lungs. The expression of chemokine CCL5 which recruits immune cells into the lungs was also reduced. Finally, EP downregulated the expression of HMGB1 in the lungs. Our results imply that EP should be further evaluated as a potential candidate for ARDS therapy.
Assuntos
Proteína HMGB1 , Piruvatos , Síndrome do Desconforto Respiratório , Humanos , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Proteína HMGB1/metabolismo , Interleucina-6 , Pandemias , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Síndrome do Desconforto Respiratório/tratamento farmacológicoRESUMO
Rosmarinic acid is a polyphenolic compound, abundantly present in herbs of the Lamiaceae family. The aim of the study was to evaluate the immunomodulatory properties of a recently developed phenethyl ester derivative of rosmarinic acid (PERA), with enhanced ability of diffusion through biological membranes, in an animal model of the central nervous system (CNS) autoimmunity. To this end, experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis was used. Daily subcutaneous administration of PERA (30 mg/kg) from day 7 to day 22 after immunization successfully ameliorated EAE induced in Dark Agouti rats, shortening the disease duration and reducing maximal, cumulative and mean clinical score. PERA efficiently reduced production of major encephalitogenic cytokines, interferon (IFN)-γ and interleukin (IL)-17, in immune cells from the CNS or the lymph nodes draining the site of immunization of EAE rats, as well as in CD4+ T cells purified from the lymph nodes. Also, PERA inhibited NO production in the CNS and the lymph nodes, as well as in macrophages and microglial cells. Finally, microglial ability to produce pro-inflammatory cytokines IL-6, and tumor necrosis factor (TNF) were also reduced by PERA. Our results clearly imply that PERA possesses anti-encephalitogenic properties. Thus, further studies on the relevance of the observed effects for the therapy of multiple sclerosis are warranted.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Ratos , Animais , Camundongos , Ésteres/uso terapêutico , Citocinas , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Ácido RosmarínicoRESUMO
Experimental autoimmune encephalomyelitis (EAE) is classically induced with complete Freund's adjuvant (CFA). The immune response against CFA has a confounding influence on the translational capacity of EAE as a multiple sclerosis model. Here, we compare clinical, cellular and molecular properties between syngeneic spinal cord homogenate (SCH)- and SCH + CFA-immunized Dark Agouti rats. EAE signs were observed earlier and the cumulative clinical score was higher without CFA. Also, a higher number of immune cells infiltrates in the spinal cords was noticed at the peak of EAE without CFA. High spinal cord abundance of CD8+CD11bc+MHC class II+ cells was detected in SCH-immunized rats. Myelin basic protein -specific response can be elicited in the cells from the lymph nodes draining the site of SCH immunization. This CFA-free EAE is a reliable multiple sclerosis model.