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

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(a dagger 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(a dagger int) mice. The secretory cell metaplasia in DBZ-treated casp8(a dagger int) animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8(a dagger int) background. Our data suggest that casp8 acts in the intestinal Notch network.