ALKBH5-YTHDF2 m6A modification axis inhibits rheumatoid arthritis progression by suppressing NLRP3

Biochem Biophys Res Commun. 2023 Aug 6:668:70-76. doi: 10.1016/j.bbrc.2023.05.087. Epub 2023 May 23.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Recently, NLRP3 has been demonstrated to be closely related to RA. The objective of our research was to analyze the specific mechanism of NLRP3 in RA. The m6A levels of NLRP3 was detected with methylated RNA immunoprecipitation (MeRIP) kit. The mRNA and protein levels of related genes were tested with RT-qPCR and Western blot. The inflammatory factors levels were detected with ELISA kits. The cell proliferative ability was measured with CCK-8 and EdU staining assays. NLRP3 levels was prominently in synovial tissues and fibroblast-like synoviocytes (FLS) from RA patients. NLRP3 silencing suppressed FLS proliferation and inflammatory factor levels. Additionally, ALKBH5 was found to bind with NLRP3, and ALKBH5 silencing suppressed FLS proliferation and inflammatory factor levels while NLRP3 overexpressing neutralized the role of ALKBH5 in FLS. Furthermore, m6A modified induced by ALKBH5 suppressed NLRP3 mRNA level through YTHDC2 in RA, and NLRP3 is a hinge factor in RA progression.

Keywords: ALKBH5; NLRP3; Rheumatoid arthritis; YTHDC2; m6A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AlkB Homolog 5, RNA Demethylase / genetics
  • AlkB Homolog 5, RNA Demethylase / metabolism
  • Arthritis, Rheumatoid* / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Humans
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • RNA-Binding Proteins / metabolism
  • Synovial Membrane / metabolism
  • Synoviocytes* / metabolism
  • Transcription Factors / metabolism

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Transcription Factors
  • ALKBH5 protein, human
  • AlkB Homolog 5, RNA Demethylase
  • YTHDF2 protein, human
  • RNA-Binding Proteins