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A novel NF-?B/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.

ABSTRACT: The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-?B activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-? and IL-1? in an NF-?B-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate I?B degradation and NF-?B activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-?B activation then significantly promoted the production of various inflammatory cytokines, including TNF-?, IL-1?, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-?B/YY1/miR-10a/NF-?B regulatory circuit that promotes the excessive secretion of NF-?B-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.

SUBMITTER: Mu N

PROVIDER: S-EPMC4731824 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.

Mu Nan N Gu Jintao J Huang Tonglie T Zhang Cun C Shu Zhen Z Li Meng M Hao Qiang Q Li Weina W Zhang Wangqian W Zhao Jinkang J Zhang Yong Y Huang Luyu L Wang Shuning S Jin Xiaohang X Xue Xiaochang X Zhang Wei W Zhang Yingqi Y

Scientific reports 20160129

The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulati ...[more]

PMID: 26821827

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Project description:Rheumatoid arthritis (RA) is a common systemic autoimmune disorder of unknown etiology, which threatens public health. The regulatory role of tripartite motif‑containing 22 (TRIM22) has been reported in multiple types of cancers and disease, but not in RA. The aim of the present study was therefore to elucidate the potential roles and underlying mechanisms of TRIM22 in fibroblast‑like synoviocytes (FLSs) in RA. The Gene Expression Omnibus database was used to examine TRIM22 mRNA expression levels in synovial tissue samples of patients with RA and healthy controls. TRIM22 and forkhead box C1 (FOXC1) mRNA and protein expression levels in normal FLSs and RA‑FLSs were assessed using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting, respectively. The Cell Counting Kit‑8 assay was used to assess cell proliferation. Cell apoptosis was analyzed using flow cytometry. The migratory and invasive abilities of RA‑FLSs were assessed using Transwell assays. Western blotting was used to analyze the protein expression levels of apoptosis‑related factors, MMP2, MMP9 and NF‑κB signaling pathway‑related proteins. Inflammatory factors levels were assessed via ELISA and RT‑qPCR. Furthermore, the JASPAR database, chromatin immunoprecipitation and the dual‑luciferase reporter assays were used to determine the interaction between FOXC1 and the TRIM22 promoter. The results of the present study demonstrated that TRIM22 expression levels were significantly elevated in the synovial tissue samples of patients with RA and RA‑FLSs. Moreover, FOXC1 was also significantly overexpressed in RA‑FLSs. TRIM22 knockdown significantly reduced cell proliferation, migration, invasion and the inflammatory response, whereas cell apoptosis was significantly increased. Furthermore, the results demonstrated that FOXC1 may have positively mediated TRIM22 expression via binding to the TRIM22 promoter. Moreover, FOXC1 overexpression significantly reversed the outcome of TRIM22 knockdown on the proliferation, apoptosis, migration, invasion and inflammation of RA‑FLSs. FOXC1 overexpression also significantly reversed the inactivation of the NF‑κB signaling pathway caused by TRIM22 knockdown. In summary, the present study demonstrated that TRIM22 was potentially activated via FOXC1, which contributed to the progression of RA via the NF‑κB signaling pathway.

Project description:ObjectiveUp-regulation of glucose metabolism has been implicated not only in tumor cell growth but also in immune cells upon activation. However, little is known about the metabolite profile in rheumatoid arthritis (RA), particularly in fibroblast-like synoviocytes (FLS). This study was undertaken to evaluate whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage.MethodsSynovium and FLS were obtained from patients with RA and patients with osteoarthritis (OA). The rate of glycolysis after stimulation of FLS with lipopolysaccharide and platelet-derived growth factor BB was measured using glycolysis stress test technology. FLS function was evaluated using a glycolysis inhibitor, 2-deoxy-d-glucose (2-DG). After stimulation of the FLS, a migration scratch assay, MTT assay, and enzyme-linked immunosorbent assay were performed to measure the effect of 2-DG on FLS migration, viability of the FLS, and cytokine secretion, respectively. IRDye 800CW 2-DG was used to assess glucose uptake in the arthritic joints and stromal cells of mice after K/BxN mouse serum transfer. The mice were injected daily, intraperitoneally, with 3-bromopyruvate (BrPa; 5 mg/kg) to assess the effect of inhibition of glycolysis in vivo.ResultsCompared to human OA FLS, the balance between glycolysis and oxidative phosphorylation was shifted toward glycolysis in RA FLS. Glucose transporter 1 (GLUT1) messenger RNA (mRNA) expression correlated with baseline functions of the RA FLS. Glucose deprivation or incubation of the FLS with glycolytic inhibitors impaired cytokine secretion and decreased the rate of proliferation and migration of the cells. In a mouse model of inflammatory arthritis, GLUT1 mRNA expression in the synovial lining cells was observed, and increased levels of glucose uptake and glycolytic gene expression were detected in the stromal compartment of the arthritic mouse joints. Inhibition of glycolysis by BrPa, administered in vivo, significantly decreased the severity of arthritis in this mouse model.ConclusionTargeting metabolic pathways is a novel approach to understanding the mechanisms of disease. Inhibition of glycolysis may directly modulate synoviocyte-mediated inflammatory functions and could be an effective treatment strategy for arthritis.

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A novel NF-?B/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.

Publications

A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.

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