Intricate mechanisms trigger scattered crypt IEC apoptosis mediated necrotizing enterocolitis pathogenesis in neonatal mice
Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B216
Abstract ID: 5468
Presenting Author:
Saravanan Subramanian , Research Assistant Professor at Univ. of Illinois Col. of Med.
Abstract:
Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal inflammatory disorder among premature infants. Intestinal epithelial cell (IEC) apoptosis contributes to NEC pathogenesis. However, how scattered crypt IEC apoptosis leads to NEC with excessive epithelial necrosis in intestinal villi and mucosa inflammation remain unclear. We developed a novel triple-transgenic mouse model, namely, 3xTg-iAPcIEC (inducible apoptosis phenotype in crypt-IEC) using doxycycline (Dox)-inducible tetO-rtTA system and vil-cre technology, for inducing tissue-specific overexpression of Fasl in IECs. We found that scattered crypt IEC apoptosis caused intestinal crypt inflammation and villous necrosis resembling NEC in neonates. This pathological progression initiated a set of NEC-associated intricate cellular and molecular pathophysiological effect including increase in Rip3 and Ifng, infiltration of CD8+ T cells, and dysbiosis with Gram-positive bacteria. Mechanistically, scattered crypt IEC apoptosis-induced IFN-γ and RIP3 activation were noted to mediate both intestinal crypt inflammation and mucosal villous necrosis, whereas CD8+ T cells and dysbiosis with Gram-positive bacteria contribute to mucosal villous necrosis. Notably, we observed that blocking any of these events protects NEC development in 3xTg-iAPcIEC mouse pups, underlining their central roles in the NEC pathogenesis. Our findings may advance knowledge in preventing or treating this devastating disorder in humans.
Intricate mechanisms trigger scattered crypt IEC apoptosis mediated necrotizing enterocolitis pathogenesis in neonatal mice
Category
Poster and Podium (Block Symposium)