2. Academic Validation
  3. Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis

Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis

  • Biomed Pharmacother. 2024 May:174:116551. doi: 10.1016/j.biopha.2024.116551.
Tiane Peng 1,  Bingtong Li 1,  Liqi Bi 2,  Fangze Zhang 3
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
  • 2 Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun 130033, China. Electronic address: bilq@jlu.edu.cn.
  • 3 Department of Gastroenterology/Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun 130033, China. Electronic address: zhangfz@jlu.edu.cn.
PMID: 38636399 DOI: 10.1016/j.biopha.2024.116551
Abstract

Background: Bicarbonate has recently been identified as a crucial factor affecting peptidylarginine deiminase (PAD) activity; however, the mechanism underlying its role in rheumatoid arthritis (RA) remains unclear. Iguratimod (IGU), a small-molecule disease-modifying anti-rheumatic drug, requires further investigation. This study aimed to explore the mechanism by which bicarbonate affects citrullination and inflammation in RA and identify new targets for IGU.

Methods: We enrolled 20 patients with RA in the study. Sodium bicarbonate cotransporter 2 (NBCe2) was detected in the peripheral blood neutrophils and peripheral blood mononuclear cells (PBMCs) of these patients. The effects of varying concentrations of IGU, methotrexate (MTX), dexamethasone (DXM), and S0859 (an NBCe2 inhibitor) on NBCe2, PAD2, PAD4, and citrullinated histone H3 (cit-H3) levels in, migration ability of, and cytokine production from neutrophils and PBMCs were examined.

Results: Our findings showed that in patients with RA, citrullinated protein production by peripheral blood neutrophils instead of PBMCs, which showed higher NBCe2 expression levels, increased with an increase in the bicarbonate concentration. In addition, tumor necrosis factor-alpha (TNF-α) promoted NBCe2 expression in neutrophils from patients with RA. Furthermore, we revealed that the inhibitory effects of IGU on neutrophil NBCe2 and cit-H3 levels, degrees of inhibition of neutrophil and PBMC migration, and suppression of interleukin 6, TNF-α, and metalloproteinase-9 secretion from neutrophil-like differentiated HL-60 cells did not substantially differ from those of MTX, DXM, and S0859 at specific doses.

Conclusions: Bicarbonate promotes protein citrullination and inflammation in RA via NBCe2, and IGU can downregulate NBCe2.

Keywords

Citrullination; Iguratimod; Methotrexate; Peptidylarginine deiminase; Sodium bicarbonate cotransporter 2; rheumatoid arthritis.

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