Sterile Inflammation drives multiple programmed cell death pathways in the gut

RUERA CAROLINA; MICULAN EMANUEL; PÉREZ FEDERICO; DUCCA GERONIMO; CARASI PAULA; CHIRDO FERNANDO GABRIEL

JOURNAL OF LEUKOCYTE BIOLOGY

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2020

0741-5400

Intestinal epithelial cells have a rapid turnover, being rapidly renewed by newly differentiated enterocytes, balanced by massive and constant removal of damaged cells by programmed cell death (PCD). The main forms of PCD are apoptosis, pyroptosis and necroptosis, with apoptosis being a non-inflammatory process, while the others drive innate immune responses. Although apoptosis is thought to be the principal means of cell death in the healthy intestine, which mechanisms are responsible for PCD during inflammation are not fully understood. To address this question, we used an in vivo model of enteropathy in wild type mice induced by a single intragastric administration 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 2h 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 of mature forms of caspase-1, IL-1β and GSDMD showed activation of pyroptosis and inhibition of caspase-1 led to decreased enterocyte death in p31-43 treated mice. There was also upregulation of RIPK3 in crypt epithelium, suggesting that necroptosis was also occurring. Taken together, these results indicate that the inflammatory response induced by p31-43 can drive multiple PCD pathways in the small intestine.