Helicobacter pyloriupregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis

Abstract

ObjectiveHelicobacter pyloriinfection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism ofH. pyloriinfection in the progression of RA.MethodsThe Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared betweenH. pylori-negative andH. pylori-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 ofH. pyloriinfection in RA progression.ResultsThe DAS-28 and ACPA levels of patients with RA in theH. pylori-positive group were significantly higher than those in theH. pylori-negative group. Polyclonal ACPA derived fromH. pylori-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found thatH. pyloriinfection 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 thePADI4gene 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 inH. pylori-infected patients with RA.ConclusionOur findings reveal a novel mechanism by whichH. pyloriinfection contributes to RA progression. Therapeutic interventions targetingH. pylorimay be a viable strategy for the management of RA.