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1.
Biomed Res Int ; 2021: 5574282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497850

RESUMO

Programmed cell death 1 ligand (PD-L1) and its receptor (PD-1) are key molecules for immunoregulation and immunotherapy. PD-L1 binding PD-1 is an effective way to regulate T or B cell immunity in autoimmune diseases such as rheumatoid arthritis (RA). In our study, we overexpressed PD-L1 by constructing a recombinant of PD-L1-lentiviral vector, which was subsequently used to transfect mouse bone marrow mesenchymal stem cells (MBMMSCs) and significantly suppressed the development of collagen-induced arthritis (CIA) in DBA/1j mice. In addition, PD-L1-transfected MBMMSCs (PD-L1-MBMMSCs) ameliorated joint damage, reduced proinflammatory cytokine expression, and inhibited T and B cell activation. Furthermore, PD-L1-MBMMSCs decreased the number of dendritic cells and increased the numbers of regulatory T cells and regulatory B cells in joints of CIA mice. In conclusion, our results provided a potential therapeutic strategy for RA treatment with PD-L1-MBMMSC-targeted therapy.


Assuntos
Artrite Experimental/terapia , Artrite Reumatoide/terapia , Antígeno B7-H1/administração & dosagem , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Células Cultivadas , Modelos Animais de Doenças , Ativação Linfocitária , Masculino , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos DBA
2.
J Immunol ; 207(7): 1755-1762, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470853

RESUMO

Conformation-specific Ags are ideal targets for mAb-based immunotherapy. Here, we demonstrate that the monomeric form of C-reactive protein (mCRP) is a specific therapeutic target for arthritis and nephritis in a murine model. Screening of >1800 anti-mCRP mAb clones identified 3C as a clone recognizing the monomeric, but not polymeric, form of CRP. The anti-mCRP mAb suppressed leukocyte infiltration in thioglycollate-induced peritonitis, attenuated rheumatoid arthritis symptoms in collagen Ab-induced arthritis model mice, and attenuated lupus nephritis symptoms in MRL/Mp-lpr/lpr lupus-prone model mice. These data suggest that the anti-mCRP mAb 3C has therapeutic potential against rheumatoid arthritis and lupus nephritis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Proteína C-Reativa/imunologia , Imunoterapia/métodos , Nefrite Lúpica/imunologia , Peritonite/imunologia , Pleura/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Artrite Reumatoide/terapia , Modelos Animais de Doenças , Humanos , Nefrite Lúpica/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Peritonite/terapia , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas , Toracentese
3.
Immunology ; 164(3): 617-636, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34351636

RESUMO

Proper regulation of B-cell function is essential for effective humoral immunity and maintenance of immune tolerance. Here, we found that FBW7 (F-box/WD40 repeat-containing protein 7) is highly expressed in germinal centre B and B1 cells, and confirmed that it has an intrinsic role in maintaining homeostasis of mature B cells and B-1 cells. FBW7 deletion led to an impairment of antibody response, and although germinal centre formation was not affected, antibody class-switch recombination and affinity maturation processes were defective. Likewise, memory immune response was severely impaired. Moreover, FBW7 ablation ameliorated the pathogenesis of an autoimmune disease model, collagen-induced arthritis, by reducing the production of anti-collagen II autoantibodies. Taken together, these data suggest that FBW7 may be an attractive target for developing new therapeutics for the treatment of autoimmune diseases.


Assuntos
Artrite Experimental/imunologia , Linfócitos B/imunologia , Proteína 7 com Repetições F-Box-WD/metabolismo , Animais , Artrite Experimental/diagnóstico , Artrite Experimental/patologia , Linfócitos B/metabolismo , Colágeno/administração & dosagem , Colágeno/imunologia , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Switching de Imunoglobulina/genética , Memória Imunológica , Masculino , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença , Ubiquitinação/imunologia
4.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343136

RESUMO

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismo
5.
Ann Rheum Dis ; 80(10): 1268-1277, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380700

RESUMO

Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Autoimunidade/imunologia , Imunoterapia , Tolerância a Antígenos Próprios/imunologia , Animais , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Experimental/prevenção & controle , Artrite Experimental/terapia , Artrite Reumatoide/prevenção & controle , Artrite Reumatoide/terapia , Doenças Assintomáticas , Dessensibilização Imunológica , Modelos Animais de Doenças , Progressão da Doença , Tolerância Imunológica/imunologia , Camundongos , Ratos , Fator Reumatoide/imunologia
6.
Front Immunol ; 12: 689057, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408746

RESUMO

Delayed-type hypersensitivity arthritis (DTHA) is a recently established experimental model of rheumatoid arthritis (RA) in mice with pharmacological values. Despite an indispensable role of CD4+ T cells in inducing DTHA, a potential role for CD4+ T cell subsets is lacking. Here we have quantified CD4+ subsets during DTHA development and found that levels of activated, pro-inflammatory Th1, Th17, and memory CD4+ T cells in draining lymph nodes were increased with differential dynamic patterns after DTHA induction. Moreover, according to B-cell depletion experiments, it has been suggested that this cell type is not involved in DTHA. We show that DTHA is associated with increased levels of B cells in draining lymph nodes accompanied by increased levels of circulating IgG. Finally, using the anti-rheumatoid agents, methotrexate (MTX) and the anti-inflammatory drug dexamethasone (DEX), we show that MTX and DEX differentially suppressed DTHA-induced paw swelling and inflammation. The effects of MTX and DEX coincided with differential regulation of levels of Th1, Th17, and memory T cells as well as B cells. Our results implicate Th1, Th17, and memory T cells, together with activated B cells, to be involved and required for DTHA-induced paw swelling and inflammation.


Assuntos
Artrite Experimental/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade Tardia/imunologia , Alérgenos/imunologia , Animais , Anticorpos/imunologia , Células Cultivadas , Feminino , , Memória Imunológica , Linfonodos/imunologia , Camundongos Endogâmicos C57BL , Soroalbumina Bovina/imunologia , Baço/imunologia
7.
Am J Physiol Cell Physiol ; 321(3): C569-C584, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288720

RESUMO

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Colestanos/farmacologia , Células Supressoras Mieloides/imunologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Comunicação Celular , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/transplante , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/antagonistas & inibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/imunologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia
8.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203838

RESUMO

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α-/-ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α-/-ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α-/-ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α-/-ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α-/-ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.


Assuntos
Artrite Experimental/enzimologia , Artrite Experimental/patologia , Domínio Catalítico , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Linfócitos T/enzimologia , Animais , Anticorpos/sangue , Artrite Experimental/sangue , Artrite Experimental/imunologia , Biomarcadores/metabolismo , Proliferação de Células , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Deleção de Genes , Imunidade , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-6/sangue , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais
9.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34185706

RESUMO

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPß activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.


Assuntos
Proteínas 14-3-3/imunologia , Macrófagos/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Proteínas 14-3-3/química , Proteínas 14-3-3/deficiência , Proteínas 14-3-3/metabolismo , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Autoimunidade , Humanos , Inflamação/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Complexos Multiproteicos/química , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Progranulinas/imunologia , Progranulinas/metabolismo , Células RAW 264.7 , Receptores Tipo II do Fator de Necrose Tumoral/química , Receptores Tipo II do Fator de Necrose Tumoral/deficiência , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/imunologia
10.
Front Immunol ; 12: 622471, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163464

RESUMO

Search for novel regulatory protein fragments with potential functional roles is required both for understanding the immune response mechanisms and the development of targeted immunotherapy. Earlier we demonstrated that the PGLYRP1/Tag7 innate immunity protein can be regarded as an inhibitor of TNFα cytotoxic activity via the interaction with its TNF receptor 1 (TNFR1). A C-terminal peptide fragment 17.1 of the molecule is responsible for this function. In this study we have identified a minimal 8-mer region of this peptide (hereinafter - 17.1A) capable to bind to TNFR1. As a result of such interaction, the cytotoxic signals induced by this receptor are blocked. Also, this peptide demonstrates an anti-inflammatory activity in vivo in the complete Freund's adjuvant (CFA)-induced arthritis model in laboratory mice. Peptide 17.1A is capable to reduce periarticular inflammation, inhibit the development of synovitis and exhibit a protective effect on cartilage and bone tissues. This peptide can turn out to be a promising medicinal agent for autoimmune arthritis and other diseases.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Fibroblastos/imunologia , Inflamação/imunologia , Peptídeos/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Animais , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Linhagem Celular , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Camundongos , Ligação Proteica , Fator de Necrose Tumoral alfa/metabolismo
11.
Elife ; 102021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34080972

RESUMO

Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we have examined the contribution of viral infection to the severity of arthritis in mice. We have provided the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV's role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (γHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we have provided the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.


Assuntos
Artrite Experimental/virologia , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/patogenicidade , Infecção Latente/virologia , Latência Viral , Fatores Etários , Animais , Antígenos CD19/genética , Antígenos CD19/metabolismo , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Citocinas/metabolismo , Progressão da Doença , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/metabolismo , Feminino , Herpesvirus Humano 4/imunologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/metabolismo , Infecção Latente/imunologia , Infecção Latente/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Índice de Gravidade de Doença , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/virologia
12.
Front Immunol ; 12: 672752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040613

RESUMO

Objective: We recently demonstrated that EBV DNA is correlated with proinflammatory responses in mice and in rheumatoid arthritis (RA) patients; hence, we utilized an RA mouse model to examine whether EBV DNA enhances the risk and severity of arthritis and to assess its immunomodulatory effects. Methods: C57BL/6J mice were treated with collagen (arthritis-inducing agent), EBV DNA 6 days before collagen, EBV DNA 15 days after collagen, Staphylococcus epidermidis DNA 6 days before collagen, EBV DNA alone, or water. Mice were then monitored for clinical signs and affected joints/footpads were histologically analysed. The relative concentration of IgG anti- chicken collagen antibodies and serum cytokine levels of IL-17A and IFNϒ were determined by ELISA. The number of cells co-expressing IL-17A and IFNϒ in joint histological sections was determined by immunofluorescence. Results: The incidence of arthritis was significantly higher in mice that received EBV DNA prior to collagen compared to mice that only received collagen. Similarly, increased clinical scores, histological scores and paw thicknesses with a decreased gripping strength were observed in groups treated with EBV DNA and collagen. The relative concentration of IgG anti-chicken collagen antibodies was significantly increased in the group that received EBV DNA 6 days prior to collagen in comparison to the collagen receiving group. On the other hand, the highest number of cells co-expressing IFNϒ and IL-17A was observed in joints from mice that received both collagen and EBV DNA. Conclusion: EBV DNA increases the incidence and severity of arthritis in a RA mouse model. Targeting mediators triggered by viral DNA may hence be a potential therapeutic avenue.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , DNA Viral/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Animais , Artrite Experimental/patologia , Artrite Experimental/virologia , Artrite Reumatoide/patologia , Artrite Reumatoide/virologia , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4 , Incidência , Camundongos , Camundongos Endogâmicos C57BL
13.
Immunology ; 164(1): 161-172, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33934341

RESUMO

The IL-7/IL-7R pathway plays a vital role in the immune system, especially in the inflammatory response. Monocytes/macrophages (osteoclast precursors) have been recently recognized as important participants in the osteoclastogenesis of rheumatoid arthritis (RA) patients. Here, we aimed to investigate the therapeutic potential of IL-7/IL-7R pathway in RA and to determine whether it could restrain osteoclastogenic functions and therefore ameliorate RA. Firstly, collagen-induced arthritis (CIA) mice were administered with IL-7Rα-target antibodies to assess their therapeutic effect on arthritis. We found that blockade of the IL-7/IL-7R pathway protected CIA mice from bone destruction in addition to inducing inflammatory remission, by altering the RANKL/RANK/OPG ratio and consequently decreasing osteoclast formation. To explore the effect and mechanism of this pathway, bone marrow cells were induced to osteoclasts and treated with IL-7, a STAT5 inhibitor or supernatants from T cells. The results showed that the IL-7/IL-7R pathway played a direct inhibitory role in osteoclast differentiation via STAT5 signalling pathway in a RANKL-induced manner. We applied flow cytometry to analyse the effect of IL-7 on T-cell RANKL expression and found that IL-7/IL-7R pathway had an indirect role in the osteoclast differentiation process by enhancing the RANKL expression on T cells. In conclusion, the IL-7/IL-7R pathway exhibited a dual effect on osteoclastogenesis of CIA mice by interacting with osteoimmunology processes and could be a novel therapeutic target for autoimmune diseases such as RA.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-7/metabolismo , Macrófagos/fisiologia , Osteoclastos/fisiologia , Receptores de Interleucina-7/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Bloqueadores/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Interleucina-7/genética , Camundongos , Terapia de Alvo Molecular , Osteogênese , Ligante RANK/metabolismo , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
14.
Front Immunol ; 12: 669856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986757

RESUMO

Effective tolerogenic intervention in Rheumatoid Arthritis (RA) will rely upon understanding the evolution of articular antigen specific CD4 T cell responses. TCR clonality of endogenous CD4 T cell infiltrates in early inflammatory arthritis was assessed to monitor evolution of the TCR repertoire in the inflamed joint and associated lymph node (LN). Mouse models of antigen-induced breach of self-tolerance and chronic polyarthritis were used to recapitulate early and late phases of RA. The infiltrating endogenous, antigen experienced CD4 T cells in inflamed joints and LNs were analysed using flow cytometry and TCRß sequencing. TCR repertoires from inflamed late phase LNs displayed increased clonality and diversity compared to early phase LNs, while inflamed joints remained similar with time. Repertoires from late phase LNs accumulated clones with a diverse range of TRBV genes, while inflamed joints at both phases contained clones expressing similar TRBV genes. Repertoires from LNs and joints at the late phase displayed reduced CDR3ß sequence overlap compared to the early disease phase, however the most abundant clones in LNs accumulate in the joint at the later phase. The results indicate CD4 T cell repertoire clonality and diversity broadens with progression of inflammatory arthritis and is first reflected in LNs before mirroring in the joint. These observations imply that antigen specific tolerogenic therapies could be more effective if targeted at earlier phases of disease when CD4 T cell clonality is least diverse.


Assuntos
Artrite Experimental/imunologia , Linfócitos T CD4-Positivos/imunologia , Evolução Clonal , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Articulações/imunologia , Linfonodos/imunologia , Tolerância a Antígenos Próprios , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Progressão da Doença , Feminino , Articulações/metabolismo , Linfonodos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Tolerância a Antígenos Próprios/genética , Fatores de Tempo
15.
J Leukoc Biol ; 110(3): 461-473, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34057740

RESUMO

Periodontitis induced by bacteria especially Porphyromonas gingivalis (P. gingivalis) is the most prevalent microbial disease worldwide and is a significant risk factor for systemic diseases such as rheumatoid arthritis (RA). RA and periodontitis share similar clinical and pathologic features. Moreover, the prevalence of RA is much higher in patients with periodontitis than in those without periodontitis. To explore the immunologic mechanism of periodontitis involved in RA, we established a mouse model of periodontitis and then induced RA. According to the results of paw thickness, arthritis clinical score, arthritis incidence, microscopic lesion using H&E staining, and micro-CT analysis, periodontitis induced by P. gingivalis promoted the occurrence and development of collagen-induced arthritis (CIA) in mice. Furthermore, periodontitis enhanced the frequency of CD19+ B cells, Th17, Treg, gMDSCs, and mMDSCs, whereas down-regulated IL-10 producing regulatory B cells (B10) in CIA mice preinduced for periodontitis with P. gingivalis. In vitro stimulation with splenic cells revealed that P. gingivalis directly enhanced differentiation of Th17, Treg, and mMDSCs but inhibited the process of B cell differentiation into B10 cells. Considering that adoptive transfer of B10 cells prevent RA development, our study, although preliminary, suggests that down-regulation of B10 cells may be the key mechanism that periodontitis promotes RA as the other main immune suppressive cells such as Treg and MDSCs are up-regulated other than down-regulated in group of P. gingivalis plus CIA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Periodontite/microbiologia , Porphyromonas gingivalis/patogenicidade , Animais , Antígenos CD19/metabolismo , Artrite Experimental/imunologia , Artrite Experimental/microbiologia , Artrite Reumatoide/diagnóstico por imagem , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/patologia , Camundongos , Células Supressoras Mieloides/metabolismo , Periodontite/diagnóstico por imagem , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
16.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805933

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the synovial joints. A highly potent antagonist of C-C chemokine receptor 5 (CCR5), maraviroc (MVC), plays an essential role in treating several infectious diseases but has not yet been evaluated for its potential effects on RA development. This study focused on evaluating the therapeutic potential of MVC on collagen-induced arthritis (CIA) in DBA/1J mice. Following CIA induction, animals were treated intraperitoneally with MVC (50 mg/kg) daily from day 21 until day 35 and evaluated for clinical score and histopathological changes in arthritic inflammation. We further investigated the effect of MVC on Th9 (IL-9, IRF-4, and GATA3) and Th17 (IL-21R, IL-17A, and RORγT) cells, TNF-α, and RANTES in CD8+ T cells in the spleen using flow cytometry. We also assessed the effect of MVC on mRNA and protein levels of IL-9, IL-17A, RORγT, and GATA3 in knee tissues using RT-PCR and western blot analysis. MVC treatment in CIA mice attenuated the clinical and histological severity of inflammatory arthritis, and it substantially decreased IL-9, IRF4, IL-21R, IL-17A, RORγT, TNF-α, and RANTES production but increased GATA3 production in CD8+ T cells. We further observed that MVC treatment decreased IL-9, IL-17A, and RORγt mRNA and protein levels and increased those of GATA3. This study elucidates the capacity of MVC to ameliorate the clinical and histological signs of CIA by reducing pro-inflammatory responses, suggesting that MVC may have novel therapeutic uses in the treatment of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Maraviroc/farmacologia , Receptores CCR5/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Fator de Transcrição GATA3/imunologia , Masculino , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Células Th17/imunologia , Células Th17/patologia , Receptor Toll-Like 9/imunologia
17.
Front Immunol ; 12: 626310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815378

RESUMO

Although B cells have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA), the precise role of B cells in RA needs to be explored further. Our previous studies have revealed that adiponectin (AD) is expressed at high levels in inflamed synovial joint tissues, and its expression is closely correlated with progressive bone erosion in patients with RA. In this study, we investigated the possible role of AD in B cell proliferation and differentiation. We found that AD stimulation could induce B cell proliferation and differentiation in cell culture. Notably, local intraarticular injection of AD promoted B cell expansion in joint tissues and exacerbated arthritis in mice with collagen-induced arthritis (CIA). Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Moreover, STAT3 bound to the promoter of the Blimp-1 gene, upregulated Blimp-1 expression at the transcriptional level, and promoted B cell differentiation. Collectively, we observed that AD exacerbated CIA by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.


Assuntos
Adiponectina/toxicidade , Artrite Experimental/enzimologia , Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/enzimologia , Linfócitos B/imunologia , Colágeno Tipo II , Ativação Enzimática , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Fosfatidilinositol 3-Quinase/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais
18.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805383

RESUMO

There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.


Assuntos
Artrite Experimental/prevenção & controle , Berberina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/prevenção & controle , Linfócitos B , Berberina/uso terapêutico , Colágeno Tipo II/toxicidade , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos DBA , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Linfócitos T/imunologia
19.
Nutrients ; 13(4)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924354

RESUMO

Anti-inflammatory potential of orally administrated bioflavonoid-robinin, active sub-stance of original drug Flaroninum™ (FL), was investigated in the combination with methotrexate (MTX) and in monotherapy in rats suffering from adjuvant-induced arthritis (AA). Robinin (kaempferol-3-O-robinoside-7-O-rhamnoside) was isolated from the aerial parts of Astragalus falcatus Lam. The monotherapy with robinin was not efficient in alleviating symptoms of AA. The combination of MTX with robinin was similarly active as MTX alone in reducing the hind paw volume and change of body weight during the whole experiment. The combination, however, reduced plasma levels of Interleukin-17Aand activity of gamma-glutamyl transferase in joint more efficiently then MTX alone. Our results demonstrate that the novel combination of robinin and MTX mildly improved the reduction of inflammation in experimental arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/farmacologia , Metotrexato/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Astrágalo (Planta)/química , Sinergismo Farmacológico , Quimioterapia Combinada , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Flores/química , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Lipídeos/administração & dosagem , Lipídeos/imunologia , Masculino , Metotrexato/uso terapêutico , Folhas de Planta/química , Ratos
20.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924467

RESUMO

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Flavonoides/uso terapêutico , Animais , Antioxidantes/metabolismo , Bovinos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Colágeno Tipo II , Citocinas/sangue , Citocinas/metabolismo , Feminino , Flavonoides/farmacologia , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxido Dismutase/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
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