Two Main Cellular Components in Rheumatoid Arthritis: Communication Between T Cells and Fibroblast-Like Synoviocytes in the Joint Synovium

Tu, Jiajie; Wei, Huang; Zhang, Weiwei; Mei, Jiawei; Chen, Zhu

doi:10.3389/fimmu.2022.922111

Cited by 23 publications

(13 citation statements)

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“…22 Macrophages and T cells interact closely with RA-FLSs in the joint synovium of patients with RA. 4,23 MIR22-overexpressing RA-FLSs indirectly repressed M1 proinflammatory marker CD86 while inducing M2 antiinflammatory marker CD206 in THP-1 cell-derived macrophages (Figure 2L and M and Supplementary Figure 2E). In addition, the ratio of CD4 + T cell subtypes Th1/Th2 and Th17/Treg was also indirectly diminished by MIR22-overexpressing RA-FLSs (Figure 2O-R).…”

Section: Resultsmentioning

confidence: 96%

Epigenetic Regulatory Axis MIR22‐TET3‐MTRNR2L2 Represses Fibroblast‐Like Synoviocyte–Mediated Inflammation in Rheumatoid Arthritis

Fang,

Huang,

Zhu

et al. 2024

Arthritis & Rheumatology

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ObjectiveThe specific role of fibroblast‐like synoviocytes (FLS) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, MIR22, TET3, and MTRNR2L2, in RA‐FLS.MethodsThe expression of MIR22, TET3 and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by FISH, qPCR, IHC and western blot. Mir22‐/‐ and Tet3+/‐ mice were used to establish CAIA model. Mir22 angomir and Tet3 siRNA were used to illustrate the therapeutic effects on arthritis using CIA model. Bioinformatics, luciferase reporter assay, 5hmC dot blotting, ChIP‐qPCR and hMeDIP‐qPCR were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2.ResultsThe Mir22‐/‐ CAIA model and RA‐FLS‐related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA‐FLS by binding to its 3′UTR in TET3. The Tet3+/‐ mice‐established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the pro‐inflammatory effect of TET3 in RA. In addition, CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its pro‐inflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA‐FLS.ConclusionThe key role of the MIR22‐TET3‐MTRNR2L2 pathway in RA‐FLS provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLS.

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Section: Resultsmentioning

confidence: 96%

Epigenetic Regulatory Axis MIR22‐TET3‐MTRNR2L2 Represses Fibroblast‐Like Synoviocyte–Mediated Inflammation in Rheumatoid Arthritis

Fang,

Huang,

Zhu

et al. 2024

Arthritis & Rheumatology

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“…For example, lung and oesophageal fibroblasts are responsive to LIGHT and IL-13, which can be secreted by CD4+ T cells in asthma or EoE (Antunes et al, 2018;Wen et al, 2019). On the other hand, the ability of fibroblasts to modulate T or B cell responses may be an important factor in RA, ILD and skin inflammation, amongst other diseases (Lai et al, 2021;Tu et al, 2022;Xu et al, 2022). In their cross-tissue fibroblast analysis, Korsunsky et al (2022) reported a cluster of inflammatory fibroblasts that are common to lung, intestine, joints and salivary glands and found that these cells express CXCL10 and CCL19.…”

Section: Leukocytesmentioning

confidence: 99%

Novel fibroblast phenotypes in homeostasis and chronic inflammation: From functions to potential regulators

Miki

Manresa

2023

The Journal of Physiology

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Fibroblasts are essential components of the stroma, sustaining a variety of tissues and being key to the process of tissue repair after injury. Their role in tissue repair has been attributed to their ability to acquire a contractile, extracellular matrix‐producing phenotype known as myofibroblasts. This property is primarily dependent on their response to the pleiotropic cytokine transforming growth factor‐β1. Until recently, the potential role of fibroblasts in other homeostatic and disease‐related processes was less well understood. Although in vitro studies indicated that fibroblasts are able to respond to and secrete inflammatory mediators, definitive evidence of their contribution to chronic inflammation was limited. However, the emergence of techniques that allow exploration of tissues at the single cell level has challenged the previous paradigms on fibroblast identity and functions, and has led to the discovery of significant diversity, showing the presence of fibroblasts with alternate transcriptional profiles in a variety of tissues. These studies have also suggested potential roles of novel fibroblast subtypes as regulators of epithelial homeostasis and renewal, inflammatory cell infiltration and activation, and antigen presentation. Here, we provide a comprehensive review of the recent literature on fibroblast diversity in the digestive tract, skin, lungs and joints. We also review evidence of their contribution to the regulation of homeostasis and chronic inflammation, as well as their interactions with other cells in various tissue compartments. We discuss evidence of different factors involved in the control of fibroblast function, addressing the role of various cytokines, transcription factors and epigenetic changes, as well as microenvironmental factors, including extracellular matrix stiffness, hypoxia, and metabolic shifts.

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“…RA-FLS exhibit a metabolic profile parallel to some tumors, thriving in a hypoxic environment with increased production of oxygen radicals and cytokines [ 12 , 13 , 14 ]. Under stressful conditions, FLS has the potential to initiate, coordinate, and perpetuate inflammatory processes through complex interactions with adaptive immune response cells [ 5 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Complete Freund’s Adjuvant Induces a Fibroblast-like Synoviocytes (FLS) Metabolic and Migratory Phenotype in Resident Fibroblasts of the Inoculated Footpad at the Earliest Stage of Adjuvant-Induced Arthritis

González-Chávez

Chaparro-Barrera

Alvarado-Jáquez

et al. 2023

Cells

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The fibroblast-like synoviocytes (FLS) have a crucial role in the pathogenesis of Rheumatoid Arthritis (RA); however, its precise mechanisms remain partially unknown. The involvement of the fibroblast in activating adjuvant-induced arthritis (AA) has not been previously reported. The objective was to describe the participation of footpads’ fibroblasts in the critical initial process that drives the AA onset. Wistar rats were injected with Complete Freund’s Adjuvant (CFA) or saline solution in the hind paws’ footpads and euthanized at 24 or 48 h for genetic and histological analyses. Microarrays revealed the differentially expressed genes between the groups. The CFA dysregulated RA-linked biological processes at both times. Genes of MAPK, Jak-STAT, HIF, PI3K-Akt, TLR, TNF, and NF-κB signaling pathways were altered 24 h before the arrival of immune cells (CD4, CD8, and CD68). Key markers TNF-α, IL-1β, IL-6, NFκB, MEK-1, JAK3, Enolase, and VEGF were immunodetected in fibroblast in CFA-injected footpads at 24 h but not in the control group. Moreover, fibroblasts in the CFA inoculation site overexpressed cadherin-11, which is linked to the migration and invasion ability of RA-FLS. Our study shows that CFA induced a pathological phenotype in the fibroblast of the inoculation site at very early AA stages from 24 h, suggesting a prominent role in arthritis activation processes.

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Two Main Cellular Components in Rheumatoid Arthritis: Communication Between T Cells and Fibroblast-Like Synoviocytes in the Joint Synovium

Cited by 23 publications

References 94 publications

Epigenetic Regulatory Axis MIR22‐TET3‐MTRNR2L2 Represses Fibroblast‐Like Synoviocyte–Mediated Inflammation in Rheumatoid Arthritis

Epigenetic Regulatory Axis MIR22‐TET3‐MTRNR2L2 Represses Fibroblast‐Like Synoviocyte–Mediated Inflammation in Rheumatoid Arthritis

Novel fibroblast phenotypes in homeostasis and chronic inflammation: From functions to potential regulators

Complete Freund’s Adjuvant Induces a Fibroblast-like Synoviocytes (FLS) Metabolic and Migratory Phenotype in Resident Fibroblasts of the Inoculated Footpad at the Earliest Stage of Adjuvant-Induced Arthritis

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