Notch inhibition counteracts Paneth cell death in absence of caspase-8

Virchows Archiv : an International Journal of Pathology
M K JeonN Gassler

Abstract

Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.

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Citations

Apr 21, 2019·Cancers·Elke KaemmererNikolaus Gassler
Aug 14, 2020·Stem Cell Research & Therapy·Xianglin MeiMeiying Li
Nov 12, 2020·Cell Proliferation·Erpeng Yang, Jun Shen

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