title: Epithelial cell-intrinsic Notch signaling plays an essential role in the maintenance of gut immune homeostasis.
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.
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba, Chiba 260-8670, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Obata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takahashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Ebisawa
authors.forename: Kisa
authors.initials: K
authors.lastname: Kakiguchi
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yonemura
authors.forename: Toshi
authors.initials: T
authors.lastname: Jinnohara
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanaya
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Masumi
authors.initials: M
authors.lastname: Ohmae
authors.forename: Koji
authors.initials: K
authors.lastname: Hase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; C497571:Rbpj protein, mouse; D051880:Receptors, Notch