〔Abstract〕 To explore the regulation of interleukin 8 (IL-8) secretion by peptidylarginine deiminase 4 (PADI4) and its effect on the pathogenesis of systemic lupus erythematosus (SLE). Methods qRT-PCR was used to compare the expression levels of IL-8 in neutrophils between healthy controls (HC) and SLE patients. ELISA was used to detect IL-8 secretion levels in the serum of HC and SLE patients, the correlation between serum IL-8 and SLE related serological indicators in lupus patients was analyzed. ELISA was used to detect the effect of HC or SLE serum on IL-8 secretion by neutrophils. Using PADI4-specific inhibitor GSK484 in primary neutrophils, or in PADI4-knockdown neutrophil-like HL-60 cells (dHL-60), IL-8 stimulated by N-formyl-met-leu-phe (fMLP) or immune complexes (ICs) was detected. Results Compared with HC, IL-8 was significantly higher expressed in neutrophils of SLE patients. Serum IL-8 levels significantly increased in lupus patients and were positively correlated with serum IgM levels. Serum from SLE patients induced neutrophils to secrete more IL-8. PADI4 inhibitor could upregulate the production of IL-8 in neutrophils. In dHL-60 cells, knockdown of PADI4 led to a significant increase in IL-8 secretion. Conclusion The proinflammatory cytokine IL-8 is highly expressed in neutrophils and serum of SLE patients, regulated by PADI4 and correlated with lupus serological indicators. IL-8 plays a role in the development of SLE through inflammatory responses, and PADI4/IL-8 provides new thinking for SLE monitoring and therapy.