Endoplasmic reticulum (ER) stress is commonly observed in intestinal epithelial cells (IECs) and can, if excessive, cause spontaneous intestinal inflammation as shown by mice with IEC-specific deletion of X-box-binding protein 1 (Xbp1), an unfolded protein response-related transcription factor. In this study, Xbp1 deletion in the epithelium (Xbp1ΔIEC ) is shown to cause increased expression of natural killer group 2 member D (NKG2D) ligand (NKG2DL) mouse UL16-binding protein (ULBP)-like transcript 1 and its human orthologue cytomegalovirus ULBP via ER stress-related transcription factor C/EBP homology protein. Increased NKG2DL expression on mouse IECs is associated with increased numbers of intraepithelial NKG2D-expressing group 1 innate lymphoid cells (ILCs; NK cells or ILC1). Blockade of NKG2D suppresses cytolysis against ER-stressed epithelial cells in vitro and spontaneous enteritis in vivo. Pharmacological depletion of NK1.1+ cells also significantly improved enteritis, whereas enteritis was not ameliorated in Recombinase activating gene 1-/-;Xbp1ΔIEC mice. These experiments reveal innate immune sensing of ER stress in IECs as an important mechanism of intestinal inflammation.

Original languageEnglish
Pages (from-to)2985-2997
Number of pages13
JournalThe Journal of experimental medicine
Issue number10
Early online date2 Oct 2017
Publication statusPublished - 2 Oct 2017


  • Animals
  • Carrier Proteins/metabolism
  • Endoplasmic Reticulum/metabolism
  • Enteritis/etiology
  • Gene Deletion
  • Histocompatibility Antigens Class I/metabolism
  • Inflammation/metabolism
  • Intestinal Mucosa/metabolism
  • Membrane Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily K/physiology
  • Stress, Physiological/physiology
  • Up-Regulation
  • X-Box Binding Protein 1/physiology


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