Epithelial cell-intrinsic Notch signaling plays an essential role in the maintenance of gut immune homeostasis

Yuuki Obata, Daisuke Takahashi, Masashi Ebisawa, Kisa Kakiguchi, Shigenobu Yonemura, Toshi Jinnohara, Takashi Kanaya, Yumiko Fujimura, Masumi Ohmae, Koji Hase, Hiroshi Ohno

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38 Citations (Scopus)

Abstract

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-J ΔIEC), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis characterized by the accumulation of Th17 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-J ΔIEC mice. Furthermore, bacterial translocation was evident in the colonic mucosa of RBP-J ΔIEC mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-J ΔIEC 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 Hes1, a transcriptional repressor of p27 Kip1 and p57 Kip2. Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation.

Original languageEnglish
Pages (from-to)2427-2436
Number of pages10
JournalJournal of Immunology
Volume188
Issue number5
DOIs
Publication statusPublished - 2012 Mar 1
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Obata, Y., Takahashi, D., Ebisawa, M., Kakiguchi, K., Yonemura, S., Jinnohara, T., Kanaya, T., Fujimura, Y., Ohmae, M., Hase, K., & Ohno, H. (2012). Epithelial cell-intrinsic Notch signaling plays an essential role in the maintenance of gut immune homeostasis. Journal of Immunology, 188(5), 2427-2436. https://doi.org/10.4049/jimmunol.1101128