Sterile inflammation drives multiple programmed cell death pathways in the gut

RUERA, CAROLINA N.; MICULÁN, EMANUEL; PÉREZ, FEDERICO; DUCCA, GERÓNIMO; CARASI, PAULA; CHIRDO, FERNANDO G.

JOURNAL OF LEUKOCYTE BIOLOGY

FEDERATION AMER SOC EXP BIOL

Año: 2020

0741-5400

Intestinal epithelial cells have a rapid turnover, being rapidly renewed by newly differentiatedenterocytes, balanced by massive and constant removal of damaged cells by programmed celldeath (PCD). The main forms of PCD are apoptosis, pyroptosis, and necroptosis, with apoptosisbeing a noninflammatory process, whereas the others drive innate immune responses. Althoughapoptosis is thought to be the principal means of cell death in the healthy intestine, which mechanismsare responsible for PCD during inflammation are not fully understood. To address thisquestion, we used an in vivo model of enteropathy in wild-type mice induced by a single intragastricadministration of the p31-43 gliadin peptide, which is known to elicit transient MyD88,NLRP3, and caspase-1-dependent mucosal damage and inflammation in the small intestine. Here,we found increased numbers of TUNEL+ cells in the mucosa as early as 2 h after p31-43 administration.Western blot and immunofluorescence analysis showed the presence of caspase-3-mediated apoptosis in the epithelium and lamina propria. In addition, the presence ofmature formsof caspase-1, IL-1𝛽, and gasdermin D showed activation of pyroptosis and inhibition of caspase-1led to decreased enterocyte death in p31-43-treated mice. Therewas also up-regulation of RIPK3in crypt epithelium, suggesting that necroptosis was also occurring. Taken together, these resultsindicate that the inflammatory response induced by p31-43 can drive multiple PCD pathways inthe small intestine.