Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation.
Matute, Juan D
Gomez Del Moral, Manuel
Glickman, Jonathan N
The Journal of experimental medicine
Rockefeller University Press
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Hosomi, S., Grootjans, J., Tschurtschenthaler, M., Krupka, N., Matute, J. D., Flak, M. B., Martinez-Naves, E., et al. (2017). Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation.. The Journal of experimental medicine, 214 (10), 2985-2997. https://doi.org/10.1084/jem.20162041
Endoplasmic reticulum (ER) stress is commonly observed in intestinal epithelial cells (IEC) 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 (UPR)-related transcription factor. Here, Xbp1 deletion in the epithelium (Xbp1ΔIEC) is shown to cause increased expression of natural-killer group 2 member D (NKG2D) ligand (NKG2DL) murine UL16-binding protein like transcript 1 (MULT1) and its human orthologue cytomegalovirus UL16-binding protein (ULBP) via ER stress-related transcription factor C/EBP homology protein (CHOP). Increased NKG2DL expression on mouse IECs is associated with increased numbers of intraepithelial NKG2D-expressing group 1 ILCs. 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, while enteritis was not ameliorated in recombinase activating gene 1 (Rag1)–/–;Xbp1ΔIEC mice. These studies reveal innate immune sensing of ER stress in IEC as an important mechanism of intestinal inflammation.
Intestinal Mucosa, Endoplasmic Reticulum, Animals, Mice, Inbred BALB C, Mice, Transgenic, Mice, Enteritis, Inflammation, Carrier Proteins, Membrane Proteins, Histocompatibility Antigens Class I, Up-Regulation, Gene Deletion, Stress, Physiological, NK Cell Lectin-Like Receptor Subfamily K, X-Box Binding Protein 1
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (648889)
External DOI: https://doi.org/10.1084/jem.20162041
This record's URL: https://www.repository.cam.ac.uk/handle/1810/270164