<p>Peptidylarginine deiminase (PAD) is an enzyme, which citrullinates arginine residues of proteins. PAD4 is known to be an important factor in the induction of neutrophil extracellular traps (NETs), which are implicated in the pathogenesis of various inflammatory diseases. PAD2 is also reportedly involved in the pathogenesis of inflammatory diseases, but the details are not fully understood. In this study, we investigated the pathogenic roles of PAD2 and PAD4 in inflammatory bowel disease using a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. PAD2- and PAD4-deficient (PAD2KO and PAD4KO) mice were generated by CRISPR-Cas9-mediated genomic editing. Colitis was induced by an intrarectal injection of TNBS. TNBS injection produced severe colitis, accompanied by body weight loss, increase in myeloperoxidase activity, and inflammatory cytokine expression in wild-type (WT) mice. In contrast, the severity of colitis with these inflammatory responses was significantly reduced in either PAD2KO or PAD4KO mice. NETs formation in peritoneal neutrophils was significantly suppressed in PAD4KO but not PAD2KO mice compared with WT mice. In contrast, macrophage extracellular traps formation in peritoneal macrophages was affected neither PAD2KO nor PAD4KO mice. In conclusion, PAD2 and PAD4 contribute to the pathogenesis of TNBS-induced colitis. PAD4 is involved in NET formation while PAD2 is not involved in the NET formation, suggesting that PAD2 may contribute to the progression of colitis via a mechanism different from NETs formation and PAD4.</p>