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

Nan Mu,Wangqian Zhang,Jinkang Zhao,Yong Zhang,Yingqi Zhang,Cun Zhang,Luyu Huang,Shuning Wang,Wei Zhang,Xiaochang Xue,Weina Li,Meng Li,Jintao Gu,Xiaohang Jin,Qiang Hao,Zhen Shu,Tonglie Huang

doi:10.1038/srep20059

Abstract

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 downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, 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-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-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.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease in which fibroblast-like synoviocytes (FLSs), a specialized cell type located in synovial joints, play crucial roles in the damage, destruction and deformation of cartilage and joints
Kawano and colleagues reported that miR-124 ameliorated adjuvant-induced arthritis (AIA) by suppressing RANKL and NFATc1, making miR-124 a candidate for the treatment of human RA24. miR-30a-3p could play a critical role in the autoimmune responses that occur in rheumatoid arthritis (RA) by regulating B cell-activating factor (BAFF) expression[25]
We predict that a novel TNF-α /NF-κ B/miR-10a/NF-κ B regulatory circuit exists in FLSs, which contributes to the exaggerated activation of the NF-κ B signaling pathway and plays a critical role in inflammatory responses in RA

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease in which fibroblast-like synoviocytes (FLSs), a specialized cell type located in synovial joints, play crucial roles in the damage, destruction and deformation of cartilage and joints. During the progression of RA, constant inflammatory responses occur in the synovial membrane; the proliferative and apoptotic properties of FLSs are changed, and the cell number is greatly increased. These cells, together with other immune cells, including macrophages, dendritic cells, lymphocytes, mast cells and platelets, can disrupt immune homeostasis and create an inflammatory environment in the synovium, which attracts more immune cells and, eventually contributes to cartilage damage and joint destruction[3,4]. We predict that a novel TNF-α /NF-κ B/miR-10a/NF-κ B regulatory circuit exists in FLSs, which contributes to the exaggerated activation of the NF-κ B signaling pathway and plays a critical role in inflammatory responses in RA. The aim of this study was to verify the detailed molecular mechanism of miR-10a in this regulatory circuit and, provide a novel potential therapeutic target for the treatment of RA

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