Abstract
Methyltransferase-like 3 (METTL3), an RNA N6-methyladenosine (m6A) methyltransferase, is essential for the m6A mRNA modification. As a key enzyme of m6A methylation modification, METTL3 has been implicated in immune and inflammation regulation. However, little is known of the role and underlying mechanism of METTL3 in rheumatoid arthritis (RA). The aim of the present study is to elucidate the function and potential mechanism of METTL3 in RA pathogenesis. We used quantitative real-time polymerase chain reaction to detect the expression of METTL3 in RA patients and controls as well as the macrophage cell line. CCK-8 was used for cell proliferation assay. Enzyme-linked immunosorbent assay (ELISA) was adopted to estimate the generation of IL-6 and TNF-α in macrophages. Western blot and immunofluorescence were applied to evaluate the activation of NF-κB in macrophages. The expression of METTL3 was significantly elevated in patients with RA. It was positively associated with CRP and ESR, two common markers for RA disease activity. Besides, LPS could enhance the expression and biological activity of METTL3 in macrophages, while overexpression of METTL3 significantly attenuated the inflammatory response induced by LPS in macrophages. Moreover, the effect of METTL3 on LPS-induced inflammation in macrophages was dependent on NF-κB. This study firstly demonstrates the critical role of METTL3 in RA, which provides novel insights into recognizing the pathogenesis of RA and a promising biomarker for RA.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease with chronic and reduplicated joint destruction, which is a highly disabling disease because of joint deformity and loss of function [1]
We screened the expression of m6A methylation-related genes in the Peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by quantitative real-time PCR, including genes of Methyltransferase-like 3 (METTL3), METTL14, FTO, AlkB homologue 5 (ALKBH5), YTHDF1, and YTHDF2
It has been well documented that multiple factors are associated with inflammation and immune disorders in RA, including genetic factors, environmental factors, and epigenetic deregulation [21, 22]
Summary
Rheumatoid arthritis (RA) is an autoimmune disease with chronic and reduplicated joint destruction, which is a highly disabling disease because of joint deformity and loss of function [1]. Joint inflammation can cause redness, swelling, pain, and joint deformity [2]. Many studies have suggested that dysregulation of the immune system, including abnormal activation and T and B lymphocytes, mast cells, and macrophages, is closely associated with the development of RA [4]. High levels of autoantibodies generated by dysregulated B cells can cause lung injuries, such as anticitrullinated protein antibodies [5, 6]. Inflammatory cells can be attracted and recruited to inflammatory sites under stimulation of considerable mediators from macrophages and mast cells. Sustained and chronic inflammation leads to joint injuries and deformity [1]. It is essential to identify novel and promising biomarkers for the early diagnosis and targeted therapy of RA patients
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