Epithelial Cell-Intrinsic Notch Signaling Plays an Essential Role in the Maintenance of Gut Immune Homeostasis.

Intestinal epithelial cells (IECs) have important functions as the first line of defense against diverse microorganisms on the luminal surface. Impaired integrity of IEC has been implicated in increasing the risk for inflammatory disorders in the gut. Notch signaling plays a critical role in the maintenance of epithelial integrity by regulating the balance of secretory and absorptive cell lineages, and also by facilitating epithelial cell proliferation. We show in this article that mice harboring IEC-specific deletion of Rbpj (RBP-JΔIEC), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis character-ized by the accumulation of Thl7 cells in colonic lamina propria. Intestinal bacteria are responsible for the development of colitis, because their depletion with antibiotics prevented the development of colitis in RBP-JΔIEC mice. Furthermore, bacterial trans-location was evident in the colonic mucosa of RBP-JΔIEC mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-JΔIEC mice displayed increase in intestinal permeability after rectal administration of FITC-dextran. In addition to the defect in physical barrier, loss of Notch signaling led to arrest of epithelial cell turnover caused by downregulation of Hesl, a transcriptional repressor of p27Klp2 and p57Klp2. Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation. [ABSTRACT FROM AUTHOR]