ATP Mediates Pyroptosis in the Intestinal Mucosal System During Colitis

Abstract

Damage-associated molecular patterns (DAMPs) are molecules released from damaged or dying cells that contribute to inflammation and cell death. Extracellular ATP, a type of DAMP, has been studied primarily in the context of pyroptosis in monocytes. This study aimed to investigate the role of ATP as a DAMP in mediating pyroptosis within the intestinal mucosal system. Colitis was induced in mice by administering dextran sodium sulfate, followed by analysis of ATP levels and with the expression of pyroptosis-related proteins. Colonic epithelial cells were treated with ATP to assess cell death and pyroptosis levels. Mice with colitis exhibited elevated ATP levels in the colon and serum. Additionally, the expression of pyroptosis-related mediators was significantly upregulated in the colons of these mice. In vitro, ATP treatment increased cell death and mitochondrial dysfunction in colonic epithelial cells. ATP also enhanced inflammatory and pyroptosis responses in these cells, while the expression of apoptosis mediator proteins remained unchanged. Notably, ATP did not further enhance flagellin-induced inflammation. These findings demonstrate that ATP levels are elevated in colitis and that ATP functions as a DAMP to induce pyroptosis in intestinal epithelial cells. This study also highlights a self-propagating cycle where ATP released during pyroptosis triggers further pyroptosis in adjacent cells, exacerbating the condition. Importantly, this study extends our understanding of ATP-mediated pyroptosis to the context of the intestinal mucosal system.