Promotive Role of Dominant‐Negative Fas‐Associated Death Domain Protein Mutants in Anti‐CD3 Antibody‐Induced Murine Hyperacute Enteritis

Inflammatory bowel disease (IBD) represents a prevalent chronic intestinal inflammatory disorder governed by multifactorial regulation, in which aberrant activation and dysregulation of the intestinal immune system exert pivotal roles. Previous studies have demonstrated that intraperitoneal administration of anti‐CD3 antibody in mice elicits acute intestinal inflammation and diarrhea, accompanied by elevated expression of pro‐inflammatory cytokine transcripts, tissue edema, and expansion of intraepithelial lymphocytes (IELs). However, the molecular mechanisms by which death domain adaptor proteins regulate intestinal immune homeostasis and inflammatory responses remain incompletely understood. In this study, we identified Fas‐associated death domain protein (FADD) as a critical modulator in anti‐CD3 antibody‐induced hyperacute colitis. Our data revealed that anti‐CD3 antibody triggered ultra‐rapid intestinal injury characterized by vascular congestion and mucosal edema in wild‐type mice. Notably, the tissue damage induced by anti‐CD3 antibody was predominantly localized to the small intestine, with the jejunum being the most severely affected segment. Intriguingly, mice harboring a dominant‐negative mutant form of FADD (FADD‐DN) exhibited significantly exacerbated mucosal edema during the acute injury phase upon anti‐CD3 antibody challenge, indicating that FADD‐DN mice are more susceptible to anti‐CD3‐induced intestinal inflammation. Collectively, these findings establish FADD as a potential key molecular target for the therapeutic intervention of inflammatory bowel disease.