Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes

Ai, Rizi; Laragione, Teresina; Hammaker, Deepa; Boyle, David L.; Wildberg, André; Maeshima, Keisuke; Palescandolo, Emanuele; Krishna, Vinod; Pocalyko, David; Whitaker, John W.; Bai, Yuchen; Nagpal, Sunil; Bachman, Kurtis E.; Ainsworth, Richard I.; Wang, Mengchi; Ding, Bo; Gulko, Pércío S.; Wang, Wei; Firestein, Gary S.

doi:10.1038/s41467-018-04310-9

Cited by 135 publications

(151 citation statements)

References 45 publications

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“…Fibroblast‐like synoviocytes (FLS) are the most abundant cell type in inflamed synovial tissue and are key effector cells in rheumatoid arthritis (RA; Noss & Brenner, ; You, Koh, Leng, Kim, & Bucala, ). In RA, FLS are epigenetically altered and develop an oncogenic phenotype, resulting in chronic inflammation, proliferative synovitis, and joint damage (Ai et al, ; Bottini & Firestein, ; Kasperkovitz et al, ). In B .…”

Section: Introductionmentioning

confidence: 99%

“…Fibroblast-like synoviocytes (FLS) are the most abundant cell type in inflamed synovial tissue and are key effector cells in rheumatoid arthritis (RA; Noss & Brenner, 2008;You, Koh, Leng, Kim, & Bucala, 2018). In RA, FLS are epigenetically altered and develop an oncogenic phenotype, resulting in chronic inflammation, proliferative synovitis, and joint damage (Ai et al, 2018;Bottini & Firestein, 2013;Kasperkovitz et al, 2005). In B. burgdorferi-infected mice, synovial fibroblasts are a dominant source of IFN-inducible genes, such as Tcell chemokines CXCL9 and CXCL10 (Lochhead et al, 2012;Paquette et al, 2017).…”

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confidence: 99%

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Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Lochhead

Ordóñez

Arvikar

et al. 2019

Cellular Microbiology

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Lyme arthritis (LA), a late disease manifestation of Borrelia burgdorferi infection, usually resolves with antibiotic therapy. However, some patients develop proliferative synovitis lasting months to several years after spirochetal killing, called postinfectious LA. In this study, we phenotyped haematopoietic and stromal cell populations in the synovial lesion ex vivo and used these findings to generate an in vitro model of LA using patient‐derived fibroblast‐like synoviocytes (FLS). Ex vivo analysis of synovial tissue revealed high abundance of IFNγ‐producing T cells and NK cells. Similar to marked IFNγ responses in tissue, postinfectious LA synovial fluid also had high levels of IFNγ. HLA‐DR‐positive FLS were present throughout the synovial lesion, particularly in areas of inflammation. FLS stimulated in vitro with B. burgdorferi, which were similar to conditions during infection, expressed 68 genes associated primarily with innate immune activation and neutrophil recruitment. In contrast, FLS stimulated with IFNγ, which were similar to conditions in the postinfectious phase, expressed >2,000 genes associated with pathogen sensing, inflammation, and MHC Class II antigen presentation, similar to the expression profile in postinfectious synovial tissue. Furthermore, costimulation of FLS with B. burgdorferi and IFNγ induced greater expression of IL‐6 and other innate immune response proteins and genes than with IFNγ stimulation alone. These results suggest that B. burgdorferi infection, in combination with IFNγ, initiates the differentiation of FLS into a highly inflammatory phenotype. We hypothesise that overexpression of IFNγ by lymphocytes within synovia perpetuates these responses in the postinfectious period, causing proliferative synovitis and stalling appropriate repair of damaged tissue.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Lochhead

Ordóñez

Arvikar

et al. 2019

Cellular Microbiology

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“…Most epidemiologic records suggest that the incidence of RA is about 0.5-1.0%, and around 70 to 80% of RA patients have autoantibodies, indicating that RA represents itself as an autoimmune disease [18]. Considerable efforts to define the epigenome of RA have concentrated on FLS of the synovial intimal lining that invade the cartilage, demonstrating an exceptional aggressive phenotype in RA patients [19]. During this study, we were set to examine the functions of PVT1 in RA-FLSs to further clarify the specific mechanisms linked to the pathogenesis of RA.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of long non-coding RNA PVT1 induces apoptosis of fibroblast-like synoviocytes through modulating miR-543-dependent SCUBE2 in rheumatoid arthritis

Wang

Kong

et al. 2020

J Orthop Surg Res

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Background: Rheumatoid arthritis (RA), a kind of autoimmune disorder, is featured by many physical symptoms and proliferation of fibroblast-like synoviocytes (FLSs). The relevance of long non-coding RNAs (lncRNAs) in the progression of RA has been probed. Hence, the goal of this report was to investigate the action of plasmacytoma variant translocation 1 (PVT1), a lncRNA, in FLSs and the basic mechanism. Methods: Initially, RA rats were developed to evaluate the expression of PVT1, microRNA-543 (miR-543), and signal peptide-CUB-EGF-like containing protein 2 (SCUBE2) in synovial tissues. Enhancement or loss of PVT1 or miR-543 was achieved to explore their effects on proliferation, cell cycle, and apoptosis of FLSs. The interaction between PVT1 and miR-543 and between miR-543 and its putative target SCUBE2 was examined to elucidate the correlations. Finally, the protein expression of proliferation-and apoptosis-associated genes were assessed by western blot assays. Results: PVT1 was overexpressed in synovial tissues from RA patients through microarray expression profiles. The PVT1 and SCUBE2 expression was boosted, and miR-543 was reduced in synovial tissues of rats with RA. PVT1 specifically bound to miR-543, and miR-543 negatively regulated SCUBE2 expression. Overexpression of PVT1 or silencing of miR-543 enhanced SCUBE2 expression, thereby promoting proliferation and interleukin-1β (IL-1β) secretion, while inhibiting apoptosis rate of FLSs. Conversely, si-SCUBE2 reversed the role of miR-543 inhibitor. Conclusion:The key findings support that PVT1 knockdown has the potency to hinder RA progression by inhibiting SCUBE2 expression to sponge miR-543.

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“…Mechanisms such as histone modifications, DNA methylation and chromatin remodeling together govern the epigenetic landscape that dictate the outcome of cell fate (19). Epigenetics reprogramming of FLS in particular is suggested to be a major mediator of FLS transformation, RA persistence and therapeutic resistance (5,8). Recent large-scale genome-wide studies have incontrovertibly established that FLS transformation is associated with epigeneticremodeling.…”

Section: Discussionmentioning

confidence: 99%

“…The transformed FLS are major source of proinflammatory cytokines, cartilage degrading enzymes as well as the osteoblast activating factor and thereby possess an ability to induce synovitis, arthritis and osteoporosis (1)(2)(3)(4). Recent genome wide studies have established that multiple signaling and transcriptional factors with potential pathogenic activities exhibit epigenomic reprogramming in the RA FLS (5)(6)(7). The inflammatory milieu in RA synovium promotes an abnormal epigenetic landscape, modulates chromatin accessibility and favors the pathogenic processes observed in RA FLS such as invasion, migration and production of proinflammatory mediators (1,8,9).…”

Section: Introductionmentioning

confidence: 99%

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

Gangishetti

Ramírez-Pérez

Jones

et al. 2020

Preprint

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Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established proinflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence. on a Hi-Seq 2500 System (University of Georgia Genomics Core) to generate data in FastQ file format. In order to study chromatin accessibility changes due to chronic inflammation, we downloaded FastQ files from a DNase I hypersensitivity sequencing (DNase-seq) experiment of wild-type FLS and inflamed FLS from inflammatory arthritis mouse model (Table S1). FastQ files from the ATAC-seq and DNase-seq experiments were analyzed using the Strand NGS sequence analysis pipeline first by aligning the sequences to the mouse genome, mm10 build, followed by removal of duplicate reads.Peak calling and gene annotation were performed by MACS2 algorithm using a padding distance of 5 kb from the transcription start sites of genes. Pathway analysis. Ingenuity Pathway Analysis tool was used to predict the canonical regulatory pathways and diseases and functions associated with the SAGs and SRGs (38). Functional protein-protein analysis was performed using STRING protein-protein interaction plugin on Cytoscape, an open source software platform for visualizing complex networks pathway analysis tool (39, 40). Open-source tool, ChEA3 that uses ChIP-seq experiments from the ENCODE database was used to predict transcription factors associations with SAG and SRGs (17).

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Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes

Cited by 135 publications

References 45 publications

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Interferon‐gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast‐like synoviocytes into immune effector cells

Knockdown of long non-coding RNA PVT1 induces apoptosis of fibroblast-like synoviocytes through modulating miR-543-dependent SCUBE2 in rheumatoid arthritis

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

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