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1.
PLoS One ; 15(9): e0239396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966314

RESUMO

Despite recent progress in the treatment of rheumatoid arthritis (RA), many patients still fail to achieve remission or low disease activity. An imbalance between auto-reactive effector T cells (Teff) and regulatory T cells (Treg) may contribute to joint inflammation and damage in RA. Therefore, restoring this balance is a promising approach for the treatment of inflammatory arthritis. Accordingly, our group has previously shown that the combination of TGF-ß-releasing microparticles (MP), rapamycin-releasing MP, and IL-2-releasing MP (TRI MP) can effectively increase the ratio of Tregs to Teff in vivo and provide disease protection in several preclinical models. In this study TRI MP was evaluated in the collagen-induced arthritis (CIA) model. Although this formulation has been tested previously in models of destructive inflammation and transplantation, this is the first model of autoimmunity for which this therapy has been applied. In this context, TRI MP effectively reduced arthritis incidence, the severity of arthritis scores, and bone erosion. The proposed mechanism of action includes not only reducing CD4+ T cell proliferation, but also expanding a regulatory population in the periphery soon after TRI MP administration. These changes were reflected in the CD4+ T cell population that infiltrated the paws at the onset of arthritis and were associated with a reduction of immune infiltrate and inflammatory myeloid cells in the paws. TRI MP administration also reduced the titer of collagen antibodies, however the contribution of this reduced titer to disease protection remains uncertain since there was no correlation between collagen antibody titer and arthritis score.


Assuntos
Artrite Experimental/prevenção & controle , Interleucina-2/farmacologia , Microesferas , Sirolimo/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Autoanticorpos/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Contagem de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Interleucina-2/química , Masculino , Camundongos , Sirolimo/química , Fator de Crescimento Transformador beta/química
2.
PLoS Pathog ; 16(7): e1008591, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645118

RESUMO

Reactive arthritis, an autoimmune disorder, occurs following gastrointestinal infection with invasive enteric pathogens, such as Salmonella enterica. Curli, an extracellular, bacterial amyloid with cross beta-sheet structure can trigger inflammatory responses by stimulating pattern recognition receptors. Here we show that S. Typhimurium produces curli amyloids in the cecum and colon of mice after natural oral infection, in both acute and chronic infection models. Production of curli was associated with an increase in anti-dsDNA autoantibodies and joint inflammation in infected mice. The negative impacts on the host appeared to be dependent on invasive systemic exposure of curli to immune cells. We hypothesize that in vivo synthesis of curli contributes to known complications of enteric infections and suggest that cross-seeding interactions can occur between pathogen-produced amyloids and amyloidogenic proteins of the host.


Assuntos
Artrite Infecciosa/imunologia , Proteínas de Bactérias/imunologia , Febre Tifoide/imunologia , Animais , Anticorpos Antinucleares/imunologia , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Infecciosa/metabolismo , Proteínas de Bactérias/biossíntese , Intestino Grosso/imunologia , Intestino Grosso/microbiologia , Camundongos , Febre Tifoide/metabolismo
3.
PLoS Genet ; 16(6): e1008788, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32497089

RESUMO

The control of chronic inflammation is dependent on the possibility of limiting bystander activation of autoreactive and potentially pathogenic T cells. We have identified a non-sense loss of function single nucleotide polymorphism in the C-type lectin receptor, Clec4b, and have shown that it controls chronic autoimmune arthritis in rat models of rheumatoid arthritis. Clec4b is specifically expressed in CD4+ myeloid cells, mainly classical dendritic cells (DCs), and is defined by the markers CD4+/MHCIIhi/CD11b/c+. We found that Clec4b limited the activation of arthritogenic CD4+αßT cells and the absence of Clec4b allowed development of arthritis already 5 days after adjuvant injection. Clec4b sufficient CD4+ myeloid dendritic cells successfully limited the arthritogenic T cell expansion immediately after activation both in vitro and in vivo. We conclude that Clec4b expressed on CD4+ myeloid dendritic cells regulate the expansion of auto-reactive and potentially pathogenic T cells during an immune response, demonstrating an early checkpoint control mechanism to avoid autoimmunity leading to chronic inflammation.


Assuntos
Artrite Experimental/genética , Lectinas Tipo C/fisiologia , Ativação Linfocitária , Linfócitos T/imunologia , Animais , Artrite Experimental/imunologia , Efeito Espectador , Células Cultivadas , Células Dendríticas/imunologia , Lectinas Tipo C/genética , Mutação com Perda de Função , Ratos
4.
Cell Prolif ; 53(7): e12824, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32567730

RESUMO

OBJECTIVES: Bone marrow edema is a universal manifestation of rheumatoid arthritis (RA), and its pathological essence is a bone marrow lesion (BML) formed by various bone marrow (BM) immune cells. Neutrophils play an important role in inflammatory arthritis, but the role and mechanism of neutrophils in BML are not clear. MATERIALS AND METHODS: Granulocyte colony-stimulating factor (G-CSF) -/- mice and wild type (WT) C57BL/6 mice were immunized for collagen-induced arthritis (CIA). Histological scores of arthritis were evaluated. Immunohistochemistry staining with anti-Ly6G was conducted. Neutrophil extracellular traps (NETs) in joint sections were determined by immunofluorescence staining. BM neutrophils were isolated for flow cytometry and NETosis induction in vitro. RESULTS: Histological study showed significant neutrophil infiltrations in BML of CIA mice. Inhibition of BM neutrophil production by G-CSF knock out can obstruct the induction of BML and CIA. In addition to abundant infiltrated NETs intra-articular, remarkable NETosis primed BM neutrophils were infiltrated in BML of CIA mice, which was positively related to bone erosion. Neutrophils derived from G-CSF-/- mice have diminished ability of NETs formation in vitro, while G-CSF induction can enhance its capacity of NETs formation. CONCLUSIONS: We propose for the first time that the overproduced BM neutrophils in CIA mice are primed for NETosis in a G-CSF dependent manner, and these pathogenic cells may have an important role in inflammatory arthritis. Blocking this pathological process could be a potential strategy for the treatment of RA.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Medula Óssea/imunologia , Neutrófilos/imunologia , Animais , Células da Medula Óssea/imunologia , Colágeno/imunologia , Armadilhas Extracelulares/imunologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
5.
Nat Commun ; 11(1): 1995, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332732

RESUMO

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.


Assuntos
Artrite Reumatoide/prevenção & controle , Permeabilidade da Membrana Celular/efeitos dos fármacos , Disbiose/complicações , Haptoglobinas/antagonistas & inibidores , Mucosa Intestinal/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Precursores de Proteínas/antagonistas & inibidores , Adulto , Animais , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Experimental/prevenção & controle , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Translocação Bacteriana/efeitos dos fármacos , Translocação Bacteriana/imunologia , Células CACO-2 , Permeabilidade da Membrana Celular/imunologia , Estudos de Coortes , Estudos Transversais , Disbiose/imunologia , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Haptoglobinas/metabolismo , Voluntários Saudáveis , Humanos , Íleo/citologia , Íleo/efeitos dos fármacos , Íleo/microbiologia , Íleo/patologia , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Precursores de Proteínas/sangue , Precursores de Proteínas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
6.
Clin Immunol ; 214: 108395, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32240819

RESUMO

Immune related adverse events (irAEs) have been observed with all checkpoint inhibitors and are very frequent. The evidences coming from experimental models of congenital or acquired deficiency of CTLA-4 or from PD-1 knock-out mice, provided all the informations to interpret the organ or systemic manifestations (endocrine, or systemic autoimmune chronic inflammatory diseases-ACIDs) observed in trials as well as in registries of cohorts treated with anti-CTLA-4 or anti-PD-1/PD-L1 inhibitors, or combination therapies. Finally the concern raised by cancers occurring in patients with autoimmune diseases (Systemic Lupus Erythematosus, Myositis, Rheumatoid Arthritis, Psoriatic Arthritis, Vasculitis, Scleroderma, Polymyalgia Rheumatica and others) and how to deal with immunotherapy was discussed. The biological knowledges acquired with the immunotherapy trials, have paved to way to better treat autoimmune diseases in patients developing cancer during the autoimmune illness. Immunotherapy without Autoimmunity is the unmet need within our reach in the future.


Assuntos
Abatacepte/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tolerância a Antígenos Próprios/efeitos dos fármacos , Abatacepte/farmacologia , Abatacepte/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Artrite Experimental/imunologia , Artrite Psoriásica/imunologia , Artrite Psoriásica/terapia , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Células Clonais/imunologia , Modelos Animais de Doenças , Humanos , Inflamação , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Neoplasias/complicações , Neoplasias/imunologia , Neoplasias/terapia , Doenças Reumáticas/induzido quimicamente , Doenças Reumáticas/complicações , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Proteínas Supressoras de Tumor/fisiologia
7.
Nat Commun ; 11(1): 1998, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332730

RESUMO

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/imunologia , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Etanol/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Ácido Acético/metabolismo , Ácido Acético/farmacologia , Animais , Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Autoanticorpos/imunologia , Autoimunidade/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Colágeno/administração & dosagem , Colágeno/imunologia , Etanol/metabolismo , Feminino , Humanos , Camundongos , Fatores de Proteção , Tolerância a Antígenos Próprios/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
8.
Life Sci ; 246: 117420, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32050085

RESUMO

PURPOSE: We intend to assess the effect of the conditioned medium of Caffeine pulsed MSCS in the amelioration of rheumatoid arthritis (RA)-afflicted rats. METHODS: MSCs were incubated with 0, 0.1, 0.5 or 1 mM Caffeine for 2 weeks. RA was induced by the injection of complete Freund's adjuvant (CFA) into the base of the tail of Wistar rats. According to in vitro studies, RA rats were intraperitoneally treated with MSCs, Caffeine (0.5 mM) pulsed MSCs or vehicle on day 14 when all rats had shown signs of RA. RESULTS: Our results suggest that the least effective dose concentration of Caffeine that can induce potent anti-inflammatory property in the MSC population is 0.5 mM. Without any significant impact on the vitality or MScs' marker, Caffeine at this concentration could induce lower levels of IFN-γ, IL-6, and IL-1ß and a higher level of IDO, TGF-ß, and IL-10 compared to other groups. Therefore, MSCs pulsed with Caffeine at 0.5 mM concentration was selected for in vitro studies. Caffeine pulsed MSCs could reduce the severity of the disease and improve weight-gaining more profoundly than treatment with MSCs alone. Furthermore, Caffeine pulsed MSCs caused a significant reduction in the serum levels C-reactive protein, Nitric oxide, Myeloperoxidase, TNF-α and conversely led a significant increase in the levels of IL-10 more prominent than the similar findings brought about by MSCs alone. CONCLUSION: In general, caffeine-treated MSCs may be a promising strategy for cell-based therapy of RA.


Assuntos
Artrite Reumatoide/terapia , Cafeína/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Artrite Experimental/imunologia , Artrite Experimental/terapia , Artrite Reumatoide/imunologia , Relação Dose-Resposta a Droga , Imunomodulação , Masculino , Ratos , Ratos Wistar
9.
J Leukoc Biol ; 107(6): 933-939, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32040234

RESUMO

Systemic TNF neutralization can be used as a therapy for several autoimmune diseases. To evaluate the effects of cell type-restricted TNF blockade, we previously generated bispecific antibodies that can limit TNF secretion by myeloid cells (myeloid cell-specific TNF inhibitors or MYSTIs). In this study several such variable domain (VH) of a camelid heavy-chain only antibody-based TNF inhibitors were compared in relevant experimental models, both in vitro and in vivo. Pretreatment with MYSTI-2, containing the anti-F4/80 module, can restrict the release of human TNF (hTNF) from LPS-activated bone marrow-derived macrophage (BMDM) cultures of humanized TNF knock-in (mice; hTNFKI) more effectively than MYSTI-3, containing the anti-CD11b module. MYSTI-2 was also superior to MYSTI-3 in providing in vivo protection in acute toxicity model. Finally, MYSTI-2 was at least as effective as Infliximab in preventing collagen antibody-induced arthritis. This study demonstrates that a 33 kDa bispecific mini-antibody that specifically restricts TNF secretion by macrophages is efficient for amelioration of experimental arthritis.


Assuntos
Anticorpos Monoclonais/farmacologia , Artrite Experimental/terapia , Antígeno CD11b/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Cadeias Pesadas de Imunoglobulinas/farmacologia , Células Progenitoras Mieloides/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Inibidores do Fator de Necrose Tumoral/farmacologia , Animais , Antirreumáticos/farmacologia , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Expressão Gênica , Humanos , Infliximab/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Células Progenitoras Mieloides/imunologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
J Vis Exp ; (156)2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32091008

RESUMO

Neutrophils are a major member of the innate immune system and play pivotal roles in host defense against pathogens and pathologic inflammatory reactions. Neutrophils can be recruited to inflammation sites via the guidance of cytokines and chemokines. Overwhelming infiltration of neutrophils can lead to indiscriminate tissue damage, such as in rheumatoid arthritis (RA). Neutrophils isolated from peritoneal exudate respond to a defined chemoattractant, N-formyl-Met-Leu-Phe (fMLP), in vitro in Transwell or Zigmond chamber assays. The air pouch experiment can be used to evaluate the chemotaxis of neutrophils towards lipopolysaccharide (LPS) in vivo. The adjuvant-induced arthritis (AA) mouse model is frequently used in RA research, and immunohistochemical staining of joint sections with anti-myeloperoxidase (MPO) or anti-neutrophil elastase (NE) antibodies is a well-established method to measure neutrophil infiltration. These methods can be used to discover promising therapies targeting neutrophil migration.


Assuntos
Movimento Celular , Neutrófilos/citologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Movimento Celular/efeitos dos fármacos , Separação Celular , Modelos Animais de Doenças , Articulações/patologia , Camundongos Endogâmicos C57BL , N-Formilmetionina Leucil-Fenilalanina/análogos & derivados , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia
11.
Int J Oral Sci ; 12(1): 5, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32024813

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease affecting 1% of the world population and is characterized by chronic inflammation of the joints sometimes accompanied by extra-articular manifestations. K/BxN mice, originally described in 1996 as a model of polyarthritis, exhibit knee joint alterations. The aim of this study was to describe temporomandibular joint (TMJ) inflammation and damage in these mice. We used relevant imaging modalities, such as micro-magnetic resonance imaging (µMRI) and micro-computed tomography (µCT), as well as histology and immunofluorescence techniques to detect TMJ alterations in this mouse model. Histology and immunofluorescence for Col-I, Col-II, and aggrecan showed cartilage damage in the TMJ of K/BxN animals, which was also evidenced by µCT but was less pronounced than that seen in the knee joints. µMRI observations suggested an increased volume of the upper articular cavity, an indicator of an inflammatory process. Fibroblast-like synoviocytes (FLSs) isolated from the TMJ of K/BxN mice secreted inflammatory cytokines (IL-6 and IL-1ß) and expressed degradative mediators such as matrix metalloproteinases (MMPs). K/BxN mice represent an attractive model for describing and investigating spontaneous damage to the TMJ, a painful disorder in humans with an etiology that is still poorly understood.


Assuntos
Artrite Experimental/patologia , Artrite Reumatoide/patologia , Osso e Ossos/diagnóstico por imagem , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/lesões , Microtomografia por Raio-X/métodos , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Modelos Animais de Doenças , Humanos , Imagem por Ressonância Magnética , Metaloproteinase 8 da Matriz/imunologia , Camundongos , Camundongos Transgênicos , Articulação Temporomandibular/metabolismo , Tomografia Computadorizada por Raios X
12.
Arthritis Res Ther ; 22(1): 16, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31973752

RESUMO

BACKGROUND: Proper blocking of toll-like receptor (TLR) activation during disease progression has been reported to have inhibitory effect on the pathogenesis of rheumatoid arthritis (RA). We tested whether the TLR4 inhibitor TAK-242 had potential as a remedy for rheumatoid arthritis. METHODS: The therapeutic effect of TAK-242 was tested in vitro using the human rheumatoid fibroblast-like synoviocyte (FLS) line MH7A or primary human FLS and in an adjuvant-induced arthritis (AIA) rat model. RESULTS: TAK-242 dose dependently inhibited the increased expression of IL-6, IL-8, MMP-1, and VEGF in LPS-stimulated MH7A cells. It also inhibited the expression of IL-6 and IL-8 in poly(I:C), TLR3 activator-stimulated primary FLS, but not in IL-1ß-stimulated primary FLS. These findings suggest that TAK-242 blocks a specific signaling pathway to some degree. Further, TAK-242 slightly inhibited mobilization of NF-κB into nuclei. In the AIA rat model, TAK-242 significantly reversed the body weight and paw thickness of AIA rats to the normal state at a dose of 5 mg/kg, but not at 3 mg/kg, and reduced the increased serum level of IL-6 and VEGF in AIA rats. It also significantly ameliorated inflammatory symptoms of joint tissues at day 21 of treatment, according to histology and RT-PCR. CONCLUSIONS: Based on the drug repositioning concept, TAK-242, which is used for the treatment of TLR4-mediated inflammatory diseases, shows potential for cost-effective development as a remedy for rheumatoid arthritis or to control the progression of RA.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide , Sulfonamidas/farmacologia , Sinoviócitos/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Células Cultivadas , Feminino , Humanos , Ratos , Ratos Wistar
13.
Int J Mol Med ; 45(2): 417-428, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894253

RESUMO

Humulus japonicus (HJ) is a widely used herbal medicine in Asia with anti­oxidative, anti­microbial, and anti­inflammatory effects. We investigated the potential therapeutic effects of HJ in rheumatoid arthritis (RA) using a mouse model of collagen­induced arthritis (CIA) and a lipopolysaccharide­stimulated murine macrophage cell line (RAW 264.7). The CIA mice were administered 300 mg/kg HJ orally starting 3 days prior to second immunization. The clinical and histopathological findings were assessed in the paw of CIA mice. The levels of autoantibodies and inflammatory markers were determined in the plasma and cell culture supernatant, respectively. The expression at mRNA and protein levels was analyzed by reverse transcription quantitative­PCR and western blot analysis, respectively. HJ significantly decreased the gross arthritic scores and paw swelling in CIA mice. Furthermore, synovial inflammation, cartilage destruction, and bone erosion were markedly reduced by HJ. It also decreased the expression of inflammatory enzymes in both the paw of mice and RAW 264.7 cells. Moreover, the expression of genes related to all macrophages and pro­inflammatory M1 macrophage were significantly decreased, whereas the expression of anti­inflammatory M2 macrophage marker was markedly increased in the paw of HJ­treated CIA mice. In addition, HJ suppressed the levels of plasma anti­type II collagen antibody following the decreased expression of T helper type 1 (Th1) and Th2 cell­associated surface markers and cytokines in the paw. HJ also significantly inhibited the expression of IL­6 both in vitro and in vivo, followed by reduced STAT3 phosphorylation and expression in the paw of CIA mice. Finally, the expression of osteoclast­related genes was decreased in the paw of HJ­treated CIA mice. These findings suggest that HJ can play a role in suppressing the development of CIA by overall regulation of articular inflammation. This study should provide new insights into the use of HJ as a therapeutically effective natural product against RA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Humulus , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/química , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Modelos Animais de Doenças , Humulus/química , Inflamação/tratamento farmacológico , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Masculino , Camundongos , Extratos Vegetais/química , Células RAW 264.7
14.
Arthritis Rheumatol ; 72(6): 919-930, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31943941

RESUMO

OBJECTIVE: Fcγ receptors (FcγR) play important roles in both protective and pathogenic immune responses. The assembly of the CBM signalosome encompassing caspase recruitment domain-containing protein 9, B cell CLL/lymphoma 10, and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) is required for optimal FcγR-induced canonical NF-κB activation and proinflammatory cytokine release. This study was undertaken to clarify the relevance of MALT-1 protease activity in FcγR-driven events and evaluate the therapeutic potential of selective MALT-1 protease inhibitors in FcγR-mediated diseases. METHODS: Using genetic and pharmacologic disruption of MALT-1 scaffolding and enzymatic activity, we assessed the relevance of MALT-1 function in murine and human primary myeloid cells upon stimulation with immune complexes (ICs) and in murine models of autoantibody-driven arthritis and immune thrombocytopenic purpura (ITP). RESULTS: MALT-1 protease function is essential for optimal FcγR-induced production of proinflammatory cytokines by various murine and human myeloid cells stimulated with ICs. In contrast, MALT-1 protease inhibition did not affect the Syk-dependent, FcγR-mediated production of reactive oxygen species or leukotriene B4 . Notably, pharmacologic MALT-1 protease inhibition in vivo reduced joint inflammation in the murine K/BxN serum-induced arthritis model (mean area under the curve for paw swelling of 45.42% versus 100% in control mice; P = 0.0007) but did not affect platelet depletion in a passive model of ITP. CONCLUSION: Our findings indicate a specific contribution of MALT-1 protease activity to FcγR-mediated events and suggest that MALT-1 protease inhibitors have therapeutic potential in a subset of FcγR-driven inflammatory disorders.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Receptores de IgG/imunologia , Animais , Complexo Antígeno-Anticorpo/metabolismo , Plaquetas/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Células Mieloides/metabolismo
15.
Phytomedicine ; 67: 153156, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31901568

RESUMO

BACKGROUND: Baihu-Guizhi decoction (BHGZD) has been extensively used for the treatment of rheumatoid arthritis (RA) with a satisfying therapeutic effect. However, the material basis and the underlying mechanisms of BHGZD against RA have not been fully elucidated. PURPOSE: To investigate the chemical profile and the pharmacological mechanisms of BHGZD against RA. METHODS: The chemical constituents containing in BHGZD were identified using UFLC-Q-TOF-MS/MS system, and the corresponding putative targets were predicted. Then, the differentially expressed genes (DEGs) between adjuvant-induced arthritis (AIA) and normal control groups were identified using microarray analysis. After constructing the interaction network of "RA-related gene-BHGZD putative target", BHGZD candidate targets against RA were screened by topological analysis and further experimentally validated based on AIA rat model. RESULTS: A total of 41 chemical constituents were identified in the water extract of BHGZD, which were predicted to hit 1312 putative targets. Additionally, 26 DEGs between the AIA and normal control groups were defined as "RA-related genes", which were functionally involved into the imbalance of "inflammation-immune" system during RA progression. On the basis of the topological importance in the network of "RA-related gene-BHGZD putative target", 177 BHGZD candidate targets against RA were identified. Among them, TLR4, c-Fos/AP-1, IL2 and TNF had direct interactions with each other and also function as crucial components of toll-like receptor and T cell receptor signaling pathways, which may play important roles in maintaining the balance of "inflammation-immune" system. Experimentally, we verified that BHGZD dose-dependently attenuated the severity, pathological changes, as well as mechanical, cold, and heat hypersensitivities during RA progression based on the AIA rat model. Further western blot analysis demonstrated that BHGZD significantly reduced the protein levels of TLR4, c-Fos/AP-1, IL2 and TNF, which were induced by RA modeling, in the inflamed joints of AIA rats (all p<0.05). CONCLUSION: This study combining the chemical and transcriptomic profilings, target prediction, network calculation and experimental validations identifies the chemical constituents containing in BHGZD and offers the convincing evidence that BHGZD may ameliorate RA partially by restoring the balance of "inflammation-immune" system and subsequently reversing the pathological events during RA progression through regulating the TLR4-c-Fos-IL2-TNF axis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacologia , Espectrometria de Massas em Tandem/métodos , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Masculino , Ratos Endogâmicos Lew
16.
Mod Rheumatol ; 30(2): 232-238, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31441345

RESUMO

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial inflammation in multiple joints. Autoantibodies (Abs) are the hallmark of RA, and as disease-specific and diagnostic markers, rheumatoid factor and anti-citrullinated protein antibody (ACPA) are produced pre-clinically, but their pathogenic roles in RA remain elusive. In this review, we focus on one of the candidate autoantigens in RA; glucose-6-phosphate isomerase (GPI). The arthritogenic role of GPI has been confirmed in two different mouse models: the K/BxN- and GPI-induced arthritis models. Both anti-GPI Abs and citrullinated-GPI peptide Abs have been detected in human RA. Studies conducted in these rodent models have confirmed that the pathogenesis of arthritis involves the localization of autoantigens not only in the joints but also in the circulation. In this review, we revisit and summarize the arthritogenic relevance of GPI in animal RA models and in human RA, and extend the discussion to joint-specific inflammation.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoimunidade , Glucose-6-Fosfato Isomerase/imunologia , Animais , Autoanticorpos/imunologia , Humanos
17.
J Ethnopharmacol ; 250: 112428, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31783137

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zishen Tongluo formula (ZTF) is simplified from the Qingluo Tongbi formula, which has been applied to treat rheumatoid arthritis (RA) in clinical practices for several decades. Our previous studies have verified the effects of ZTF on arthritis animal models. However, its mechanism of treating RA is not clear. AIM OF THE STUDY: The present study was designed to investigate the effects of ZTF on the Th17/Treg balance in RA mice and the role of the different herb groups with the effect of Zishen yangyin (YY), Huatan quyu (HT), or Qufeng chushi (QF) in ZTF. MATERIALS AND METHODS: A mouse model of collagen-induced arthritis (CIA) was established. The animals were randomly divided into the normal, model, positive drug, YY, QF, HT, and the whole compound (ZTF) groups. After oral administration for one-month, cytokine levels in the plasma and histopathological changes of the joint were measured by ELISA and hematoxylin-eosin staining, respectively. Meanwhile, the balance of Th17/Treg cells in blood, spleen or lymph nodes was detected using flow cytometry and qPCR. RESULTS: ZTF or the different functional groups could improve the joint inflammation, decrease the levels of proinflammatory cytokines, restore the balance of Th17 and Treg cells in CIA mice. However, there were some differences in each functional group: YY mainly promoted the responses of Treg cells while QF inhibited the functions of Th17 cells. Besides, HT regulated both Th17 and Treg cells to keep the immune balance. CONCLUSIONS: ZTF could notably ameliorate CIA mice by restoring the balance of Th17/Treg cells. Each functional group could target Th17 and/or Treg cells to produce synergistic/enhancement effects, and ZTF had a better holistic effect in RA treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Experimental/patologia , Citocinas/sangue , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos Endogâmicos DBA
18.
Int Immunol ; 32(1): 49-56, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31562738

RESUMO

Intestinal immunity and flora are reported to be associated with the onset of rheumatoid arthritis. However, differences in the intestinal immunity and flora dynamics between the initial peak and relapse of arthritis have not been investigated. Here we analyzed the lymphocyte populations in different lymphoid tissues, the IgA in feces, and the intestinal flora at the initial peak and the relapse phase of arthritis in a collagen-induced arthritis (CIA) mouse model. In this model compared with the control group, the percentage of RORγt+CD4+ T cells in the mesenteric lymph nodes (mLN) was increased at the initial peak but decreased at the relapse stage of arthritis, and the opposite changes were observed in the spleen. The percentage of Foxp3+CD4+ T cells was unchanged at the initial peak in both tissues but increased only in the mLN at the relapse stage. The IgA in feces increased with the progression of arthritis, and bacterial analysis revealed that some specific bacterial families were changed at the peak and relapse stages of arthritis. Finally, the immune dynamics under different arthritic conditions were examined by integrating these factors using principal component analysis (PCA). PCA showed that the immunological and intestinal flora profiles were different between the initial peak and the relapse of the arthritis. Our findings suggest that the intestinal immunity and the environment change drastically with the progress of arthritis.


Assuntos
Artrite Experimental/imunologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Imunidade Inata/imunologia , Intestinos/imunologia , Animais , Artrite Experimental/patologia , Camundongos , Camundongos Endogâmicos DBA
19.
Artigo em Inglês | MEDLINE | ID: mdl-31747539

RESUMO

Rheumatoid arthritis (RA) has a negative impact on muscle mass, and reduces patient's mobility and autonomy. Furthermore, RA is associated with metabolic comorbidities, notably in lipid homeostasis by unknown mechanisms. To understand the links between the loss in muscle mass and the metabolic abnormalities, arthritis was induced in male Sprague Dawley rats (n = 11) using the collagen-induced arthritis model. Rats immunized with bovine type II collagen were compared to a control group of animals (n = 11) injected with acetic acid and complete Freund's adjuvant. The clinical severity of the ensuing arthritis was evaluated weekly by a semi-quantitative score. Skeletal muscles from the hind limb were used for the histological analysis and exploration of mitochondrial activity, lipid accumulation, metabolism and regenerative capacities. A significant atrophy in tibialis anterior muscle fibers was observed in the arthritic rats despite a non-significant decrease in the weight of the muscles. Despite moderate inflammation, accumulation of triglycerides (P < 0.05), reduced mitochondrial DNA copy number (P < 0.05) and non-significant dysfunction in mitochondrial cytochrome c oxidase activity were found in the gastrocnemius muscle. Concomitantly, our results suggested an activation of the muscle specific E3 ubiquitin ligases MuRF-1 and MAFbx. Finally, the adipose tissue from the arthritic rats exhibited decreased PPARγ mRNA suggesting reduced adipogenic capacities. In conclusion, the reduced adipose tissue adipogenic capacity and skeletal muscle mitochondrial capacity are probably involved in the activation of protein catabolism, inhibition of myogenesis, accumulation of lipids and fiber atrophy in the skeletal muscle during RA.


Assuntos
Artrite Experimental/complicações , Artrite Reumatoide/complicações , Mitocôndrias/patologia , Atrofia Muscular/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/metabolismo , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Colágeno Tipo II/administração & dosagem , Colágeno Tipo II/imunologia , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Masculino , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
J Ethnopharmacol ; 249: 112418, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31770567

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Eriobotrya japonica (EJ) is a Chinese medicinal plant that is currently grown in Brazil. E. japonica leaves infusion is traditionally used in the treatment of inflammation; however, there are few scientific studies showing the effects of these properties on joint articular and persistent experimental inflammation. AIM OF THE STUDY: The present research had objective investigation of the effect of infusion obtained from leaves of E. japonica (EJLE) on acute and persistent experimental articular inflammation. MATERIALS AND METHODS: The Swiss mice were treated orally with EJLE and analyzed for acute pleural inflammation (30, 100, and 300 mg/kg), paw edema induced by carrageenan (100 mg/kg), acute knee inflammation induced by zymosan (100 mg/kg), and persistent inflammation induced by Complete Freund's Adjuvant (CFA) (30 and 100 mg/kg). Mechanical hyperalgesia, cold and edema were analyzed. RESULTS: The chromatographic analysis of EJLE revealed the presence of corosolic acid, oleanolic acid, and ursolic acid. EJLE presented anti-inflammatory activity in the pleurisy model, inhibiting leukocyte migration, protein extravasation and nitric oxide production. In the articular inflammation model, EJLE reduced the number of leukocytes in the joint cavity, paw edema and hyperalgesia (4 h after induction). In the persistent inflammation model induced by CFA, the extract reduced paw edema after 11 days of mechanical and cold hyperalgesia on day 6. CONCLUSIONS: The EJLE has anti-inflammatory and antihyperalgesic potential in models of acute and persistent experimental articular inflammation, making this infusion a new possibility for complementary treating acute or chronic articular inflammatory diseases.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Artralgia/tratamento farmacológico , Artrite Experimental/tratamento farmacológico , Eriobotrya/química , Extratos Vegetais/farmacologia , Administração Oral , Analgésicos/isolamento & purificação , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Artralgia/etiologia , Artrite Experimental/complicações , Artrite Experimental/imunologia , Brasil , Carragenina/administração & dosagem , Carragenina/imunologia , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Ratos , Zimosan/administração & dosagem , Zimosan/imunologia
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