DSS誘起マウス大腸炎の病態におけるpeptidylarginine deiminase2および4の保護的役割

抄録

Peptidylarginine deiminase (PAD) is an enzyme, which citrullinates arginineresidues of proteins, and is involved in extracellular traps (ETs). ETs arephenomenon in which histones and granulocyte proteins are released fromneutrophils and macrophages into the extracellular space with DNA, and areassociated with the pathogenesis of various inflammatory diseases. PAD4 isexpressed mainly in neutrophils and contributes to ETs in neutrophils while PAD2is widely expressed including macrophages. We recently showed that PAD4-derivedETs plays a detrimental role in TNBS-induced colitis. In the present study, weinvestigated the role of ETs derived from PAD2 and PAD4 in DSS-induced colitis.Colitis was induced in male mice lacking PAD2 (PAD2KO) and PAD4 (PAD4KO) mice byDSS solution for 7 days. DSS treatment caused severe colitis accompanied byweight loss, diarrhea, and bloody stool. Further, increase in MPO activity andinflammatory cytokine expression as well as induction of ETs were observed. Theseverity of colitis with increase in MPO activity and cytokine expression wassignificantly exacerbated in either PAD2KO or PAD4KO mice compared withwild-type (WT) mice. In particular, rectal bleeding were typically observed inthese KO mice. These findings suggest that PAD2 and PAD4 play the protectiverole in DSS-induced colitis. Thus, PAD2 and PAD4 may have a differentinvolvement in the pathogenesis of DSS- and TNBS-induced colitis.