METTL3 Promotes Activation and Inflammation of FLSs Through the NF-κB Signaling Pathway in Rheumatoid Arthritis.

Wen Shi,Jun Li,Shuai Luo,Cheng Huang,Xiaofeng Li,Yan Zheng,Xiaoming Meng,Yilong Zhang

doi:10.3389/fmed.2021.607585

Abstract

Rheumatoid arthritis (RA), a common autoimmune disease, is extremely damaging to human health. Fibroblast-like synoviocytes (FLSs) have a vital role in the occurrence and development of RA. Methyltransferase-like 3 (METTL3), which is a crucial component of the N6-methyladenosine (m6A) methyltransferase complex, is involved in the progression of many diseases. In this study, we explored the role of METTL3 in the inflammatory response and proliferation, invasion, and migration of FLSs. We used human RA synovial tissues and the adjuvant-induced arthritis (AIA) animal model of RA. Experimental results revealed that METTL3 expression was significantly upregulated in human RA synovial tissues and in the rat AIA model. METTL3 knockdown suppressed interleukin (IL)-6, matrix metalloproteinase (MMP)-3, and MMP-9 levels in human RA-FLSs and rat AIA-FLSs. In contrast, they were increased by METTL3 overexpression. Additionally, we found that, in FLSs, METTL3 may activate the nuclear factor (NF)-κB signaling pathway. The experimental results showed that METTL3 may promote FLS activation and inflammatory response via the NF-κB signaling pathway.

Highlights

Rheumatoid arthritis (RA), a common autoimmune dysfunction disease, is mainly a joint disease, but it involves multiple other systems [1]
We explored the role of Methyltransferase-like 3 (METTL3) in the inflammatory response and proliferation, invasion, and migration of fibroblast-like synoviocytes (FLSs)
Immunohistochemical analysis (Figure 1B) of the synovial tissues indicated that METTL3 was increased in RA compared to OA

Summary

Introduction

Rheumatoid arthritis (RA), a common autoimmune dysfunction disease, is mainly a joint disease, but it involves multiple other systems [1]. As a chronic inflammatory disorder, it involves synovial hypertrophy, severe joint damage, and loss of function [2, 3]. It often develops in middle age and is more common among women than in men [4]. The hyperproliferating FLSs release a large number of pro-inflammatory indicators, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, causing abnormal inflammation in the synovial membrane [8, 9]. METTL3 Role in RA reducing the activation and inflammatory response of FLSs is a promising therapeutic strategy for the treatment of RA [8, 12, 13]

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Conclusion