<i>Helicobacter pylori</i> upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis.

Abstract

<i>Helicobacter pylori</i> infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of <i>H. pylori</i> infection in the progression of RA. The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between <i>H. pylori</i>-negative and <i>H. pylori</i>-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of <i>H. pylori</i> infection in RA progression. The DAS-28 and ACPA levels of patients with RA in the <i>H. pylori</i>-positive group were significantly higher than those in the <i>H. pylori</i>-negative group. Polyclonal ACPA derived from <i>H. pylori</i>-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that <i>H. pylori</i> infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the <i>PADI4</i> gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in <i>H. pylori</i>-infected patients with RA. Our findings reveal a novel mechanism by which <i>H. pylori</i> infection contributes to RA progression. Therapeutic interventions targeting <i>H. pylori</i> may be a viable strategy for the management of RA.