Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.703
Filtrar
1.
Life Sci ; 261: 118459, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961230

RESUMO

Rheumatoid arthritis is a chronic, inflammatory joint disease leading to inflammation of synovial membrane that lines the joints. This inflammation further progresses and results in destruction of joints and surrounding cartilages. The underlying factors can be oxidative stress, pro-inflammatory mediators, imbalance and attenuation between various enzymes and proteins (like nuclear factor erythroid 2 related factor 2/Nrf2 and ubiquitin). Protein degradation pathways comprises of lysosomal, proteasomal pathway, and autophagosome (that are carried out in mammalian cells) are regulated through ubiquitin. Ubiquitin proteasomal system is dominating pathway for carrying out non-lysosomal proteolysis of intracellularly proteins. Fundamental processes including cell cycle progression, process of division, apoptosis, modulation of immune responses and cell trafficking are regulated by process of ubiquitination. Ubiquitin proteasomal pathway (UPP) includes ubiquitin moieties which are covalently attached to proteins and guides them proteasome for degradation. Misfolded, oxidized and damaged proteins which are responsible for critical processes, are major targets of degradation process. Any alteration in this system leads to dysregulated cellular homeostasis; progressively leading to numerous diseases including rheumatoid arthritis. Factors including TAK1, TRAF6 undergo are required for the progression of disease and thus contributes towards pathology of inflammatory disorders such as rheumatoid arthritis. This review will include all linked aspects which contribute its major role in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/metabolismo , Ubiquitinação , Animais , Artrite Reumatoide/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo
2.
PLoS One ; 15(8): e0237143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760165

RESUMO

OBJECTIVES: Abatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data. METHODS: In this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept. RESULTS: In methotrexate/Abatacept responders, 672 genes were significantly (q<0.05) dysregulated at 6 months compared to baseline. Correlation analysis highlighted 19 genes whose dysregulations were significantly associated with disease activity variation (p<0.05) and whose functions were associated with proliferation, apoptosis of cells and mitochondrial metabolism, suggesting a restoration of oxidative signaling. The other 653 gene expression changes were relative to direct or indirect effects of methotrexate/Abatacept treatment and were significantly (p<0.005) involved in pathways relative to mRNA processing, proteasome, angiogenesis, apoptosis and TCR signaling. This study highlights new mechanisms of action of methotrexate/Abatacept and may provide new therapeutic targets to prevent autoimmunity in rheumatoid arthritis.


Assuntos
Abatacepte/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Metotrexato/farmacologia , Transcriptoma/efeitos dos fármacos , Abatacepte/administração & dosagem , Abatacepte/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade
3.
Life Sci ; 258: 118164, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739467

RESUMO

High mobility group box-1 (HMGB1) protein is a diverse, single polypeptide moiety, present in mammalian eukaryotic cells. In response to stimuli, this nuclear protein is actively secreted in to the extracellular compartment or passively released by the necrotic cells, in order to mediate inflammatory responses, by forming complexes with IL-1α, IL-1ß, LPS and other moieties, and binding to RAGE, TLR and other receptor ligands, initiating downstream, signaling processes. This molecule acts as a proinflammatory cytokine and contributes to the progression of diseases like, acute lung injury, autoimmune liver damage, graft rejection immune response and arthritis. Small concentrations of HMGB1 are released during apoptosis, which facilitates oxidative regulation on Cys106, and propagates immune inactivating tolerogenic signals in the body. The review portrays the role of HMGB1 in rheumatoid arthritis, evidently supported by pre-clinical and clinical investigations, demonstrating extensive HMGB1 expression in synovial tissue and fluid as well as serum, excessive expression of transduction receptor signaling molecules, bone remodeling and uncontrolled expression of bone destroying osteoclastogenesis, resulting in destruction of articular cartilage, bone deformation and synovial proliferation, alleviating the pathogenesis in RA disease. Moreover, the review highlights the therapeutic regime targeting HMGB1, facilitating inhibition of its actions and release into the extracellular compartment, to ameliorate the destructive events that prevail in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/patologia , Proteína HMGB1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Cartilagem Articular/fisiopatologia , Proteína HMGB1/análise , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Terapia de Alvo Molecular , Osteogênese/efeitos dos fármacos
4.
Nat Med ; 26(8): 1295-1306, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601335

RESUMO

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKposTREM2high and MerTKposLYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA.


Assuntos
Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Macrófagos/imunologia , Líquido Sinovial/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Biópsia , Linhagem da Célula/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Macrófagos/metabolismo , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Líquido Sinovial/imunologia , Membrana Sinovial
5.
PLoS One ; 15(7): e0235702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634159

RESUMO

Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identify commonality in muscle gene expression between this model and muscle from RA patients. Pain behaviour and locomotor activity were measured in a collagen-induced arthritis (CIA) model of RA (n = 9) and control (n = 9) rats. Energy substrates and metabolites, total alkaline-soluble protein:DNA ratio and mRNA abundance of 46 targeted genes were also determined in Extensor digitorum longus muscle. Expression of targeted mRNAs was quantified in Vastus Lateralis muscle from RA patients (n = 7) and healthy age-matched control volunteers (n = 6). CIA rats exhibited pain behaviour (p<0.01) and reduced activity (p<0.05) compared to controls. Muscle glycogen content was less (p<0.05) and muscle lactate content greater (p<0.01) in CIA rats. The bioinformatics analysis of muscle mRNA abundance differences from the control, predicted the activation of muscle protein metabolism and inhibition of muscle carbohydrate and fatty acid metabolism in CIA rats. Compared to age-matched control volunteers, RA patients exhibited altered muscle mRNA expression of 8 of the transcripts included as targets in the CIA model of RA. In conclusion, muscle energy metabolism and metabolic gene expression were altered in the CIA model, which was partly corroborated by targeted muscle mRNA measurements in RA patients. This research highlights the negative impact of RA on skeletal muscle metabolic homeostasis.


Assuntos
Artrite Reumatoide/complicações , Músculo Esquelético/metabolismo , Doenças Musculares/etiologia , Idoso , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores , Modelos Animais de Doenças , Feminino , Glicogênio/metabolismo , Humanos , Inflamação , Locomoção , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Mialgia/etiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Transcriptoma
6.
Life Sci ; 257: 118109, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32698072

RESUMO

Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by synovial proliferation, destruction to articular cartilage and severe pain. The cannabinoids obtained from Cannabis sativa exhibited their actions via cannabinoid-1 and -2 receptors, which also provides a platform for endocannabinoids to act. The endocannabinoid system comprises endocannabinoid molecules involved in signaling processes, along with G-protein coupled receptors and enzymes associated with ligand biosynthesis, activation and degradation. The action of endocannabinoid system in immune system regulation, via primary CB2 activation, followed by inhibition of production of pro-inflammatory cytokines, auto-antibodies and MMPs, FLSs proliferation and T-cell mediated immune response, are elaborated as potential therapeutic regimes in rheumatoid arthritis. The involvement of endocannabinoid system in immune cells like, B cells, T cells and macrophages, as well as regulatory actions on sensory noniceptors to ameliorate pain is significantly highlighted in the review, elaborating the actions of endocannabinoid signaling in mitigating the disease events. The review also focuses on enhancement of endocannabinoid tone, either by inhibiting the degradation enzymes, like FAAH, MAGL, COX, CytP450, LOX, etc. or by retarding cellular uptake processes. Moreover, the review portrays the optimizing role of endocannabinoid system, in abbreviating the symptoms and complications of rheumatoid arthritis in patients and mitigating inflammation, pain and immune mediated effects significantly.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Endocanabinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Reumatoide/metabolismo , Endocanabinoides/antagonistas & inibidores , Humanos , Sistema Imunitário/metabolismo , Inflamação/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo
7.
Nature ; 582(7811): 259-264, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499639

RESUMO

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3-5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Receptor Notch3/metabolismo , Transdução de Sinais , Membrana Sinovial/patologia , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Células Endoteliais/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Receptor Notch3/antagonistas & inibidores , Receptor Notch3/deficiência , Receptor Notch3/genética , Antígenos Thy-1/metabolismo
8.
Braz J Med Biol Res ; 53(6): e9489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401927

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease of knee joints involving pain and inflammation. Rhoifolin is a plant flavonoid known to have antioxidant and anti-inflammatory properties. This study was taken to identify the effect of rhoifolin on complete Freund's adjuvant (CFA)-induced arthritis in the rat model. Treatment with rhoifolin (10 and 20 mg/kg) showed a significant improvement in the overall health parameters such as paw edema and weight loss. This improvement in morphological parameters corroborated the findings with gross morphological changes observed in the histopathological analysis. Rhoifolin treatment also caused a significant decrease in oxidative stress, evident from changes in intracellular levels of glutathione, glutathione peroxidase, malondialdehyde, and superoxide dismutase in the articular cartilage tissue. Moreover, proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin(IL)-1ß, and IL-6 showed a significant downregulation of gene expression and intracellular protein concentration levels. The NF-κB pathway showed a significant attenuation as evident in the significant reduction in the levels of NF-κB p65 and p-IκB-α. These results indicated that rhoifolin can be a natural therapeutic alternative to the extant regimens, which include non-steroidal anti-inflammatory drugs and immunosuppressants. Additionally, the antioxidant and anti-inflammatory action of rhoifolin was probably mediated by the NF-κB pathway. However, the exact target molecules of this pathway need to be determined in further studies.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citocinas/sangue , Dissacarídeos/administração & dosagem , Flavonoides/administração & dosagem , Adjuvante de Freund/administração & dosagem , Glicosídeos/administração & dosagem , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , NF-kappa B/metabolismo , Ratos , Fator de Necrose Tumoral alfa/sangue
9.
Environ Toxicol ; 35(9): 991-997, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32401414

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1ß is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1ß expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1ß in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1ß. Elevations in IL-1ß mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P1 receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1ß expression. Our results indicate that S1P promotes the expression of IL-1ß in osteoblasts via the S1P1 receptor and the JAK and STAT3 signaling pathways.


Assuntos
Interleucina-1beta/genética , Janus Quinases/metabolismo , Lisofosfolipídeos/fisiologia , Osteoblastos/metabolismo , Fator de Transcrição STAT3/metabolismo , Esfingosina/análogos & derivados , Artrite Reumatoide/metabolismo , Células Cultivadas , Humanos , Lisofosfolipídeos/farmacologia , Masculino , Osteoartrite/metabolismo , Osteoblastos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/genética
10.
Nat Rev Rheumatol ; 16(6): 316-333, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393826

RESUMO

Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.


Assuntos
Artrite Reumatoide/imunologia , Reabsorção Óssea/imunologia , Cartilagem Articular/imunologia , Fibroblastos/imunologia , Membrana Sinovial/imunologia , Sinoviócitos/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Linfócitos B/imunologia , Reabsorção Óssea/metabolismo , Caderinas/metabolismo , Cartilagem Articular/metabolismo , Metilação de DNA , Células Endoteliais/metabolismo , Epigênese Genética , Fibroblastos/metabolismo , Humanos , Macrófagos/imunologia , Terapia de Alvo Molecular , Monócitos/imunologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Osteogênese , Proteínas Tirosina Fosfatases/metabolismo , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Linfócitos T/imunologia
11.
Med Sci (Paris) ; 36(5): 465-471, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32452368

RESUMO

In the last decade, the association between the periodontitis and rheumatoid arthritis (RA) has been established, suggesting that oral microbiome plays a causal role by initiating this chronic autoimmune inflammatory disease of articulation. Both pathogenesis are similar in term of chronic inflammation, tissue breakdown and bone resorption. Molecular aspects have also revealed that citrullination, a post-translational modification catalyzed by peptidyl-arginine deiminases (PADs), is involved in both diseases. For RA, citrullinated proteins production leads to the synthesis the of anti-citrullinated protein antibodies triggering the loss of immune tolerance. In humans, five PADs have been identified. Recently, studies have found that only Porphyromonas species possess PAD. Thus, a major periodontal pathogen, Porphyromonas gingivalis, is able to generate citrullinated epitopes, and could consequently induce anti-citrullinated protein antibodies. In this review, citrullination process, periodontitis and RA are described to put them in relation with molecular, clinical and epidemiological studies establishing the association between periodontitis and RA.


Assuntos
Artrite Reumatoide/etiologia , Bactérias/enzimologia , Citrulinação/fisiologia , Microbiota/fisiologia , Boca/microbiologia , Desiminases de Arginina em Proteínas/fisiologia , Artrite Reumatoide/enzimologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/microbiologia , Bactérias/metabolismo , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Periodontite/complicações , Periodontite/enzimologia , Periodontite/microbiologia , Processamento de Proteína Pós-Traducional
13.
Nat Commun ; 11(1): 1911, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312978

RESUMO

Early diagnosis is critical to improve outcomes in rheumatoid arthritis (RA), but current diagnostic tools have limited sensitivity. Here we report a large-scale multicenter study involving training and validation cohorts of 3,262 participants. We show that serum levels of soluble scavenger receptor-A (sSR-A) are increased in patients with RA and correlate positively with clinical and immunological features of the disease. This discriminatory capacity of sSR-A is clinically valuable and complements the diagnosis for early stage and seronegative RA. sSR-A also has 15.97% prevalence in undifferentiated arthritis patients. Furthermore, administration of SR-A accelerates the onset of experimental arthritis in mice, whereas inhibition of SR-A ameliorates the disease pathogenesis. Together, these data identify sSR-A as a potential biomarker in diagnosis of RA, and targeting SR-A might be a therapeutic strategy.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/metabolismo , Biomarcadores , Receptores Depuradores Classe A/metabolismo , Animais , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator Reumatoide , Receptores Depuradores Classe A/genética , Sensibilidade e Especificidade
14.
Scand J Immunol ; 91(6): e12876, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32145086

RESUMO

Rheumatoid arthritis (RA) is a worldwide autoimmune disease. The study of its aetiology and mechanism has always been a focus topic in medicine. This research was designed to investigate the effect of E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) in rheumatoid arthritis (RA). We found in fibroblast-like synoviocytes (FLS) of RA patients, the expression of TRIM32 was significantly increased compared with its expression in osteoarthritis (OA) patients FLS. A widely used pro-inflammatory stimuli tumour necrosis factor-alpha (TNF-α) was found to promote TRIM32 expression in a time-dependent manner. Furthermore, we observed that overexpression of TRIM32 aggravated the production of pro-inflammatory cytokines in FLS, silencing of TRIM32 showed the consistent results. In addition, TRIM32 was found to activate nuclear factor κB (NF-κB) signalling pathway, and TRIM32 could interact with TNF receptor-associated factor 2 (TRAF2) to promote the K63-linked polyubiquitination of TRAF2 in RA-FLS. In conclusion, we suggested that TRIM32 as a positive regulator of inflammatory responses in RA-FLS.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/imunologia , Inflamação/metabolismo , Sinoviócitos/imunologia , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Artrite Reumatoide/imunologia , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/metabolismo , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Regulação para Cima
15.
Environ Toxicol ; 35(8): 867-878, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32198911

RESUMO

MiR-20a has been reported as a key regulator to pro-inflammatory factor release in fibroblast-like synoviocytes (FLS), which caused rheumatoid arthritis (RA). However, the molecular mechanism of miR-20a in RA remains to be further elucidated. This study aimed to investigate the roles of miR-20a in RA pathology. RA (n = 24) and osteoarthritis (OA, n = 20) and normal healthy tissues (n = 16) were collected from operation. TargetScan and dual-luciferase reporter were performed to predict and confirm the potential binding sites of miR-20a on ADAM metallopeptidase domain 10 (ADAM10). Pearson's analysis was adopted to evaluate the correlation between miR-20a and ADAM10 expression. It was found that MiR-20a was downregulated in RA tissues, and overexpressed miR-20a inhibited cell viability, migration and invasion, and the expression of inflammatory factors in RA-FLS MH7A cells. ADAM10 was identified as the target gene of miR-20a, and upregulation of ADAM10 reversed the inhibitory effects of miR-20a. In conclusion, miR-20a inhibits the progression of RA-FLS as well as the inflammatory factor expression by targeting ADAM10.


Assuntos
MicroRNAs/metabolismo , Osteoartrite/metabolismo , Sinoviócitos/metabolismo , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Artrite Reumatoide/metabolismo , Proliferação de Células/genética , Células Cultivadas , Progressão da Doença , Fibroblastos/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Osteoartrite/genética , Sinoviócitos/patologia , Regulação para Cima
16.
Immunity ; 52(3): 513-527.e8, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187519

RESUMO

Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.


Assuntos
Complemento C3/imunologia , Integrinas/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Linfócitos/imunologia , Monócitos/imunologia , Migração Transendotelial e Transepitelial/imunologia , Adulto , Idoso , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Criança , Pré-Escolar , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Integrinas/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Transdução de Sinais/imunologia
17.
Biochem J ; 477(7): 1287-1308, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32203568

RESUMO

T-cell receptor (TCR) signaling is initiated by recruiting ZAP-70 to the cytosolic part of TCR. ZAP-70, a non-receptor tyrosine kinase, is composed of an N-terminal tandem SH2 (tSH2) domain connected to the C-terminal kinase domain. The ZAP-70 is recruited to the membrane through binding of tSH2 domain and the doubly phosphorylated ITAM motifs of CD3 chains in the TCR complex. Our results show that the tSH2 domain undergoes a biphasic structural transition while binding to the doubly phosphorylated ITAM-ζ1 peptide. The C-terminal SH2 domain binds first to the phosphotyrosine residue of ITAM peptide to form an encounter complex leading to subsequent binding of second phosphotyrosine residue to the N-SH2 domain. We decipher a network of noncovalent interactions that allosterically couple the two SH2 domains during binding to doubly phosphorylated ITAMs. Mutation in the allosteric network residues, for example, W165C, uncouples the formation of encounter complex to the subsequent ITAM binding thus explaining the altered recruitment of ZAP-70 to the plasma membrane causing autoimmune arthritis in mice. The proposed mechanism of allosteric coupling is unique to ZAP-70, which is fundamentally different from Syk, a close homolog of ZAP-70 expressed in B-cells.


Assuntos
Sítio Alostérico , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Proteína-Tirosina Quinase ZAP-70/química , Proteína-Tirosina Quinase ZAP-70/metabolismo , Regulação Alostérica , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Modelos Animais de Doenças , Escherichia coli/genética , Motivo de Ativação do Imunorreceptor Baseado em Tirosina , Camundongos , Simulação de Dinâmica Molecular , Fosforilação , Mutação Puntual , Transdução de Sinais , Quinase Syk/genética , Quinase Syk/metabolismo , Proteína-Tirosina Quinase ZAP-70/genética , Domínios de Homologia de src/genética
18.
Nat Rev Nephrol ; 16(6): 352-364, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32157251

RESUMO

Tonicity-responsive enhancer-binding protein (TonEBP), which is also known as nuclear factor of activated T cells 5 (NFAT5), was discovered 20 years ago as a transcriptional regulator of the cellular response to hypertonic (hyperosmotic salinity) stress in the renal medulla. Numerous studies since then have revealed that TonEBP is a pleiotropic stress protein that is involved in a range of immunometabolic diseases. Some of the single-nucleotide polymorphisms (SNPs) in TONEBP introns are cis-expression quantitative trait loci that affect TONEBP transcription. These SNPs are associated with increased risk of type 2 diabetes mellitus, diabetic nephropathy, inflammation, high blood pressure and abnormal plasma osmolality, indicating that variation in TONEBP expression might contribute to these phenotypes. In addition, functional studies have shown that TonEBP is involved in the pathogenesis of rheumatoid arthritis, atherosclerosis, diabetic nephropathy, acute kidney injury, hyperlipidaemia and insulin resistance, autoimmune diseases (including type 1 diabetes mellitus and multiple sclerosis), salt-sensitive hypertension and hepatocellular carcinoma. These pathological activities of TonEBP are in contrast to the protective actions of TonEBP in response to hypertonicity, bacterial infection and DNA damage induced by genotoxins. An emerging theme is that TonEBP is a stress protein that mediates the cellular response to a range of pathological insults, including excess caloric intake, inflammation and oxidative stress.


Assuntos
Doenças Autoimunes/metabolismo , Dano ao DNA/fisiologia , Fatores de Transcrição NFATC/metabolismo , Estresse Fisiológico/fisiologia , Artrite Reumatoide/metabolismo , Aterosclerose/metabolismo , Infecções Bacterianas/metabolismo , Carcinoma Hepatocelular/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Proteínas de Choque Térmico , Humanos , Hiperlipidemias/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Resistência à Insulina , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/fisiologia , Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Polimorfismo de Nucleotídeo Único , Estresse Salino/fisiologia , Viroses/metabolismo
19.
Proc Natl Acad Sci U S A ; 117(10): 5532-5541, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32079724

RESUMO

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose-response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , Interleucina-17/fisiologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite Reumatoide/genética , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL2/genética , Quimiocinas CXC/genética , Fatores Quimiotáticos/genética , Fibroblastos/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Inflamação/genética , Interleucina-17/farmacologia , Interleucina-6/genética , Metaloproteinase 3 da Matriz/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , RNA Interferente Pequeno/genética , Proteínas Repressoras/genética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Líquido Sinovial , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genética , Transcriptoma/efeitos da radiação , Fator de Necrose Tumoral alfa/farmacologia
20.
Scand J Immunol ; 91(5): e12870, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32034957

RESUMO

Two novel enzyme-linked immunosorbent assays (ELISAs), designed to detect complexes containing DNA, leucocyte calprotectin and S100A12 proteins, were generated for improved specificity and rapid measurement of neutrophil extracellular traps (NETs). The assays were applied on plasma and serum samples from blood donors for establishment of reference values, and from patients with multiple myeloma (MM) or rheumatoid arthritis (RA) in order to examine putatively increased values in the two different inflammatory conditions. Although NETs were hardly detectable in healthy individuals, NET levels were as expected highly and statistically significantly increased in RA patients. The detection of statistically significantly increased NET levels in MM is a novel finding.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/metabolismo , Adulto , Idoso , Artrite Reumatoide/patologia , Doadores de Sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Projetos Piloto , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA