Hosomi, ShuheiGrootjans, JoepTschurtschenthaler, MarkusKrupka, NiklasMatute, JuanFlak, Magdalena B.Martinez-Naves, EduardoGomez del Moral, ManuelGlickman, Jonathan N.Ohira, MizukiLanier, Lewis L.Kaser, ArthurBlumberg, Richard2018-05-302017Hosomi, S., J. Grootjans, M. Tschurtschenthaler, N. Krupka, J. D. Matute, M. B. Flak, E. Martinez-Naves, 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. doi:10.1084/jem.20162041. http://dx.doi.org/10.1084/jem.20162041.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37067601Endoplasmic 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.en-USArticleJournal Article2018-05-3010.1084/jem.20162041