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1.
Nat Immunol ; 24(7): 1200-1210, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37277655

RESUMO

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1ß or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.


Assuntos
Artrite Reumatoide , Humanos , Células Cultivadas , Artrite Reumatoide/genética , Membrana Sinovial , Citocinas/metabolismo , Fibroblastos
2.
Nat Immunol ; 22(12): 1551-1562, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34811544

RESUMO

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.


Assuntos
Artrite Reumatoide/metabolismo , Ácido Aspártico/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Mitocôndrias/metabolismo , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , ADP-Ribosilação , Transferência Adotiva , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD4-Positivos/ultraestrutura , Estudos de Casos e Controles , Células Cultivadas , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Chaperona BiP do Retículo Endoplasmático/metabolismo , Feminino , Humanos , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/transplante , Mitocôndrias/ultraestrutura , Membrana Sinovial/imunologia , Membrana Sinovial/ultraestrutura , Fator de Necrose Tumoral alfa/genética
3.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061532

RESUMO

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de Trabalho
4.
Nat Immunol ; 20(4): 458-470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30890796

RESUMO

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4+ T cells, prior activation via the T cell antigen receptor limits IL-6's control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4+ T cells. Transcriptomics and chromatin immunoprecipitation-sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4+ T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4+ T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4+ T cells sense and interpret cytokine signals.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Animais , Artrite Reumatoide/enzimologia , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/enzimologia , Células CHO , Células Cultivadas , Cricetulus , Regulação da Expressão Gênica , Humanos , Memória Imunológica , Interleucina-6/fisiologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interleucina-6/fisiologia , Membrana Sinovial/imunologia , Transcrição Gênica
5.
Immunity ; 55(12): 2255-2270, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36516818

RESUMO

Significant recent progress in understanding rheumatoid arthritis (RA) pathogenesis has led to improved treatment and quality of life. The introduction of targeted-biologic and -synthetic disease modifying anti-rheumatic drugs (DMARDs) has also transformed clinical outcomes. Despite this, RA remains a life-long disease without a cure. Unmet needs include partial response and non-response to treatment in many patients, failure to achieve immune homeostasis or drug free remission, and inability to repair damaged tissues. RA is now recognized as the end of a multi-year prodromal phase in which systemic immune dysregulation, likely beginning in mucosal surfaces, is followed by a symptomatic clinical phase. Inflammation and immune reactivity are primarily localized to the synovium leading to pain and articular damage, but is also associated with a broader series of comorbidities. Here, we review recently described immunologic mechanisms that drive breach of tolerance, chronic synovitis, and remission.


Assuntos
Antirreumáticos , Artrite Reumatoide , Sinovite , Humanos , Qualidade de Vida , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/uso terapêutico , Membrana Sinovial
6.
Immunity ; 54(5): 1002-1021.e10, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33761330

RESUMO

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.


Assuntos
Proteínas do Sistema Complemento/imunologia , Fibroblastos/imunologia , Inflamação/imunologia , Membrana Sinovial/imunologia , Imunidade Adaptativa/imunologia , Animais , Artrite Reumatoide/imunologia , Linhagem Celular , Cães , Humanos , Mediadores da Inflamação/imunologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Ratos Wistar , Transdução de Sinais/imunologia
7.
Nat Immunol ; 18(9): 1025-1034, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28737753

RESUMO

Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATPlopyruvatelo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Linfócitos T/metabolismo , Trifosfato de Adenosina/metabolismo , Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Movimento Celular/imunologia , Ácidos Graxos/biossíntese , Feminino , Perfilação da Expressão Gênica , Glicólise/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Inflamação , Masculino , Pessoa de Meia-Idade , Ácido Pirúvico/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Linfócitos T/imunologia
8.
Nature ; 623(7987): 616-624, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37938773

RESUMO

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.


Assuntos
Artrite Reumatoide , Humanos , Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Citocinas/metabolismo , Inflamação/complicações , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Membrana Sinovial/patologia , Linfócitos T/imunologia , Linfócitos B/imunologia , Predisposição Genética para Doença/genética , Fenótipo , Análise da Expressão Gênica de Célula Única
9.
Immunity ; 48(6): 1220-1232.e5, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29802020

RESUMO

Despite the importance of Th17 cells in autoimmune diseases, it remains unclear how they control other inflammatory cells in autoimmune tissue damage. Using a model of spontaneous autoimmune arthritis, we showed that arthritogenic Th17 cells stimulated fibroblast-like synoviocytes via interleukin-17 (IL-17) to secrete the cytokine GM-CSF and also expanded synovial-resident innate lymphoid cells (ILCs) in inflamed joints. Activated synovial ILCs, which expressed CD25, IL-33Ra, and TLR9, produced abundant GM-CSF upon stimulation by IL-2, IL-33, or CpG DNA. Loss of GM-CSF production by either ILCs or radio-resistant stromal cells prevented Th17 cell-mediated arthritis. GM-CSF production by Th17 cells augmented chronic inflammation but was dispensable for the initiation of arthritis. We showed that GM-CSF-producing ILCs were present in inflamed joints of rheumatoid arthritis patients. Thus, a cellular cascade of autoimmune Th17 cells, ILCs, and stromal cells, via IL-17 and GM-CSF, mediates chronic joint inflammation and can be a target for therapeutic intervention.


Assuntos
Artrite Reumatoide/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Linfócitos/imunologia , Células Estromais/imunologia , Células Th17/imunologia , Animais , Artrite Reumatoide/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Humanos , Linfócitos/metabolismo , Camundongos , Células Estromais/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Células Th17/metabolismo
10.
Immunity ; 46(2): 220-232, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28228280

RESUMO

Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1ß. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.


Assuntos
Comunicação Autócrina/imunologia , Fibroblastos/imunologia , Regulação da Expressão Gênica/imunologia , Fator Inibidor de Leucemia/imunologia , Receptores de OSM-LIF/imunologia , Artrite Reumatoide/imunologia , Células Cultivadas , Citocinas/biossíntese , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Interleucina-6/imunologia , Fator de Transcrição STAT4/imunologia , Membrana Sinovial/imunologia , Transcriptoma
11.
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
12.
J Immunol ; 210(2): 135-147, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36458981

RESUMO

The aggressive phenotype exhibited by fibroblast-like synoviocytes (FLSs) is critical for the progression of joint destruction in rheumatoid arthritis (RA). Long noncoding RNAs (lncRNAs) have crucial roles in the pathogenesis of diverse disorders; however, few have been identified that might be able to control the joint damage in RA. In this study, we identified an lncRNA, ENST00000509194, which was expressed at abnormally high levels in FLSs and synovial tissues from patients with RA. ENST00000509194 positively modulates the migration and invasion of FLSs by interacting with human Ag R (HuR, also called ELAVL1), an RNA-binding protein that mainly stabilizes mRNAs. ENST00000509194 binds directly to HuR in the cytoplasm to form a complex that promotes the expression of the endocytic adaptor protein APPL2 by stabilizing APPL2 mRNA. Knockdown of HuR or APPL2 impaired the migration and invasion of RA FLSs. Given its close association with HuR and FLS migration, we named ENST00000509194 as HAFML (HuR-associated fibroblast migratory lncRNA). Our findings suggest that an increase in synovial HAFML might contribute to FLS-mediated rheumatoid synovial aggression and joint destruction, and that the lncRNA HAFML might be a potential therapeutic target for dysregulated fibroblasts in a wide range of diseases.


Assuntos
Artrite Reumatoide , RNA Longo não Codificante , Sinoviócitos , Humanos , Sinoviócitos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Membrana Sinovial/patologia , Artrite Reumatoide/patologia , Movimento Celular/genética , Fibroblastos/metabolismo , Células Cultivadas , Proliferação de Células
13.
Nature ; 570(7760): 246-251, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31142839

RESUMO

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage3-5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+ fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1- destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.


Assuntos
Artrite Reumatoide/patologia , Fibroblastos/patologia , Animais , Osso e Ossos/patologia , Endopeptidases , Feminino , Fibroblastos/classificação , Fibroblastos/metabolismo , Gelatinases/metabolismo , Humanos , Inflamação/patologia , Articulações/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , RNA-Seq , Serina Endopeptidases/metabolismo , Análise de Célula Única , Membrana Sinovial/patologia , Antígenos Thy-1/metabolismo
14.
Nature ; 572(7771): 670-675, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391580

RESUMO

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.


Assuntos
Articulações/citologia , Macrófagos/citologia , Macrófagos/fisiologia , Membrana Sinovial/citologia , Sinoviócitos/citologia , Sinoviócitos/fisiologia , Junções Íntimas/fisiologia , Animais , Artrite/imunologia , Artrite/patologia , Receptor 1 de Quimiocina CX3C/análise , Receptor 1 de Quimiocina CX3C/metabolismo , Rastreamento de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/patologia , Articulações/patologia , Macrófagos/classificação , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , RNA-Seq , Análise de Célula Única , Sinoviócitos/classificação , Sinoviócitos/metabolismo , Transcriptoma/genética
15.
Mol Cell Proteomics ; 22(5): 100540, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37019382

RESUMO

Rheumatoid arthritis (RA) is a typical autoimmune disease characterized by synovial inflammation, synovial tissue hyperplasia, and destruction of bone and cartilage. Protein glycosylation plays key roles in the pathogenesis of RA but in-depth glycoproteomics analysis of synovial tissues is still lacking. Here, by using a strategy to quantify intact N-glycopeptides, we identified 1260 intact N-glycopeptides from 481 N-glycosites on 334 glycoproteins in RA synovium. Bioinformatics analysis revealed that the hyper-glycosylated proteins in RA were closely linked to immune responses. By using DNASTAR software, we identified 20 N-glycopeptides whose prototype peptides were highly immunogenic. We next calculated the enrichment scores of nine types of immune cells using specific gene sets from public single-cell transcriptomics data of RA and revealed that the N-glycosylation levels at some sites, such as IGSF10_N2147, MOXD2P_N404, and PTCH2_N812, were significantly correlated with the enrichment scores of certain immune cell types. Furthermore, we showed that aberrant N-glycosylation in the RA synovium was related to increased expression of glycosylation enzymes. Collectively, this work presents, for the first time, the N-glycoproteome of RA synovium and describes immune-associated glycosylation, providing novel insights into RA pathogenesis.


Assuntos
Artrite Reumatoide , Glicoproteínas , Proteoma , Membrana Sinovial , Humanos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Glicopeptídeos/análise , Glicoproteínas/análise , Glicosilação , Osteoartrite/patologia , Proteômica , Membrana Sinovial/química , Membrana Sinovial/patologia , Proteoma/análise
16.
Semin Immunol ; 58: 101519, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35033462

RESUMO

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. RA mainly affects synovial joints, with inflammation of the synovial membrane (synovitis), characterised by neo-angiogenesis, hyperplasia of lining layer, and immune cell infiltration that drive local inflammation and, if untreated, can lead to joint destruction and disability. In parallel to the well-known clinical heterogeneity, the underlying synovitis can also be significantly heterogeneous, both at cellular and molecular level, which can at least in part explain why despite the availability of highly effective treatment options, a large proportion of patients are resistant to some individual treatments. The assimilation of recent high-throughput data from analysis at the single-cell level with rigorous and high-quality clinical outcomes obtained from large randomised clinical trials support the definition of disease and treatment response endotypes. Looking ahead, the integration of histological and molecular signatures from the diseased tissue into clinical algorithms may help decision making in the management of patients with Rheumatoid Arthritis in clinical practice.


Assuntos
Artrite Reumatoide , Sinovite , Humanos , Artrite Reumatoide/terapia , Sinovite/patologia , Membrana Sinovial/patologia
17.
Immunol Rev ; 302(1): 163-183, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34096076

RESUMO

Rheumatoid arthritis is an immune-mediated inflammatory disease in which fibroblasts contribute to both joint damage and inflammation. Fibroblasts are a major cell constituent of the lining of the joint cavity called the synovial membrane. Under resting conditions, fibroblasts have an important role in maintaining joint homeostasis, producing extracellular matrix and joint lubricants. In contrast, during joint inflammation, fibroblasts contribute to disease pathology by producing pathogenic levels of inflammatory mediators that drive the recruitment and retention of inflammatory cells within the joint. Recent advances in single-cell profiling techniques have transformed our ability to examine fibroblast biology, leading to the identification of specific fibroblast subsets, defining a previously underappreciated heterogeneity of disease-associated fibroblast populations. These studies are challenging the previously held dogma that fibroblasts are homogeneous and are providing unique insights into their role in inflammatory joint pathology. In this review, we discuss the recent advances in our understanding of how fibroblast heterogeneity contributes to joint pathology in rheumatoid arthritis. Finally, we address how these insights could lead to the development of novel therapies that directly target selective populations of fibroblasts in the future.


Assuntos
Artrite Reumatoide , Membrana Sinovial , Fibroblastos , Humanos , Inflamação , Mediadores da Inflamação
18.
J Biol Chem ; 299(3): 102982, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36739947

RESUMO

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and affects almost 1% of the population. Differentiated embryo-chondrocyte expressed gene-1 (DEC1) has been associated with both osteogenesis and osteoclastogenesis. RA condition is marked by inflammatory hyperplasia, and DEC1 is known to support inflammatory reactions and implicated in antiapoptosis and cell invasion. Here, our goal was to test the hypothesis that DEC1 enhances RA development induced by collagen-induced arthritis (CIA), a well-recognized protocol for developing RA animal models. DEC1+/+ and DEC1-/- mice were subjected to CIA protocol, and the development of RA condition was monitored. We found that CIA robustly induced RA phenotypes (e.g., synovial hyperplasia) and greatly increased the expression of proinflammatory cytokines such as TNF-α. However, these changes were detected in DEC1+/+ but not DEC1-/- mice. Interestingly, these very cytokines strongly induced DEC1, and such a dual role of DEC1, as an inducer for and being induced by proinflammatory cytokines, constitutes a DEC1-amplifying circuit for inflammation. Knockdown of DEC1 in human MH7A cells strongly decreased cell migration and invasion as well as the expression of genes related to RA phenotypes. The combination of DEC1-directed migration and invasion in vitro with synovial hyperplasia in vivo mechanistically establishes cellular bases on how DEC1 is involved in the development of RA phenotypes. In addition to inflammatory signaling, DEC1 functionally interacted with PI3KCA(p110α)/Akt/GSK3ß, Wnt/ß-catenin, and NFATc1. Such engagement in multiple signaling pathways suggests that DEC1 plays coordinated and integral roles in developing RA, one of the most common autoimmune diseases.


Assuntos
Artrite Experimental , Artrite Reumatoide , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Proteínas de Homeodomínio , Animais , Humanos , Camundongos , Artrite Experimental/induzido quimicamente , Artrite Experimental/genética , Artrite Reumatoide/genética , Colágeno , Citocinas/metabolismo , Fibroblastos/metabolismo , Hiperplasia/patologia , Inflamação/patologia , Membrana Sinovial/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Homeodomínio/metabolismo
19.
BMC Genomics ; 25(1): 407, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664635

RESUMO

BACKGROUND: Unraveling the intricate and tightly regulated process of adipogenesis, involving coordinated activation of transcription factors and signaling pathways, is essential for addressing obesity and related metabolic disorders. The molecular pathways recruited by mesenchymal stem cells (MSCs) during adipogenesis are also dependent on the different sources of the cells and genetic backgrounds of donors, which contribute to the functional heterogeneity of the stem cells and consequently affect the developmental features and fate of the cells. METHODS: In this study, the alteration of transcripts during differentiation of synovial mesenchymal stem cells (SMSCs) derived from fibrous synovium (FS) and adipose synovial tissue (FP) of two pig breeds differing in growth performance (German Landrace (DL)) and fat deposition (Angeln Saddleback (AS)) was investigated. SMSCs from both tissues and breeds were stimulated to differentiate into adipocytes in vitro and sampled at four time points (day 1, day 4, day 7 and day 14) to obtain transcriptomic data. RESULTS: We observed numerous signaling pathways related to the cell cycle, cell division, cell migration, or cell proliferation during early stages of adipogenesis. As the differentiation process progresses, cells begin to accumulate intracellular lipid droplets and changes in gene expression patterns in particular of adipocyte-specific markers occur. PI3K-Akt signaling and metabolic pathways changed most during adipogenesis, while p53 signaling and ferroptosis were affected late in adipogenesis. When comparing MSCs from FS and FP, only a limited number of differentially expressed genes (DEGs) and enriched signaling pathways were identified. Metabolic pathways, including fat, energy or amino acid metabolism, were highly enriched in the AS breed SMSCs compared to those of the DL breed, especially at day 7 of adipogenesis, suggesting retention of the characteristic metabolic features of their original source, demonstrating donor memory in culture. In contrast, the DL SMSCs were more enriched in immune signaling pathways. CONCLUSIONS: Our study has provided important insights into the dynamics of adipogenesis and revealed metabolic shifts in SMSCs associated with different cell sources and genetic backgrounds of donors. This emphasises the critical role of metabolic and genetic factors as important indications and criteria for donor stem cell selection.


Assuntos
Adipogenia , Células-Tronco Mesenquimais , Animais , Adipogenia/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Suínos , Transdução de Sinais , Diferenciação Celular , Perfilação da Expressão Gênica , Transcriptoma , Membrana Sinovial/metabolismo , Membrana Sinovial/citologia , Adipócitos/metabolismo , Adipócitos/citologia , Células Cultivadas , Cruzamento
20.
BMC Immunol ; 25(1): 36, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38902605

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic immune system disease with a high disability rate threatening the living quality of patients. Identifying potential biomarkers for RA is of necessity to improve the prevention and management of RA. OBJECTIVES: This study focused on miR-146b-3p evaluating its clinical significance and revealing the underlying regulatory mechanisms. MATERIALS AND METHODS: A total of 107 RA patients were enrolled, and both serum and synovial tissues were collected. Another 78 osteoarthritis patients (OA, providing synovial tissues), and 72 healthy individuals (providing serum samples) were enrolled as the control group. The expression of miR-146b-3p was analyzed by PCR and analyzed with ROC and Pearson correlation analyses evaluating its significance in diagnosis and development prediction of RA patients. In vitro, MH7A cells were treated with TNF-α. The regulation of cell proliferation, motility, and inflammation by miR-146b-3p was assessed by CCK8, Transwell, and ELISA assays. RESULTS: Significant upregulation of miR-146b-3p was observed in serum and synovial tissues of RA patients, which distinguished RA patients and were positively correlated with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-cyclic citrullinated peptide antibodies (anti-CCP), and rheumatoid factor (RF) of RA patients. TNF-α promoted the proliferation and motility of MH7A cells and induced significant inflammation in cells. Silencing miR-146b-3p alleviated the effect of TNF-α and negatively regulated the expression of HMGCR. The knockdown of HMGCR reversed the protective effect of miR-146b-3p silencing on TNF-α-stimulated MH7A cells. CONCLUSIONS: Increased miR-146b-3p served as a biomarker for the diagnosis and severity of RA. Silencing miR-146b-3p could suppress TNF-α-induced excessive proliferation, motility, and inflammation via regulating HMGCR in MH7A cells.


Assuntos
Artrite Reumatoide , Movimento Celular , Proliferação de Células , MicroRNAs , Fator de Necrose Tumoral alfa , Artrite Reumatoide/imunologia , Artrite Reumatoide/diagnóstico , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Feminino , Linhagem Celular , Regulação para Cima , Biomarcadores/metabolismo , Inflamação/imunologia , Membrana Sinovial/metabolismo , Adulto , Idoso
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