PAD4-dependent neutrophil extracellular traps dagame intestinal barrier integrity through histone protein components

Abstract Infiltrating neutrophils and neutrophil extracellular traps (NETs) accumulate in the inflamed epithelium to induce mucosal inflammation patients with inflammatory bowel diseases. The formation of NETs is initiated by peptidyl arginine deiminase 4 (PAD4), which facilitates NET generation through chromatin decondensation. We recently demonstrated that impair intestinal integrity, permeability, viability mice colitis. In addition, disruption administering DNase I or PAD4 inhibitors attenuates colitic mice. However, effect genetic loss on PAD4-mediated has not been determined chemical-induced colitis models. Moreover, specific components responsible for damage impaired barrier integrity are also unknown. Here we lacking failed produce intestine response dextran sulfate sodium (DSS)-induced This impairment PAD4-deficient ameliorated inflammation, function, integrity. Mechanistically, NETs, particularly histone components, altered junctional proteins induced cytotoxicity, resulting increased gut permeability. contrast, inhibition activity restored expression localization cell viability, thus enhancing functions. Collectively, our findings indicate histones have a detrimental role regulating function inCaco-2 monolayers vivo.