upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis.

Objective: 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 infection in the progression of RA.

Methods: The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between -negative and -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 infection in RA progression.

Results: The DAS-28 and ACPA levels of patients with RA in the -positive group were significantly higher than those in the -negative group. Polyclonal ACPA derived from -positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that 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 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 -infected patients with RA.

Conclusion: Our findings reveal a novel mechanism by which infection contributes to RA progression. Therapeutic interventions targeting may be a viable strategy for the management of RA.