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 (Xbp1^ΔIEC) 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^−/−;Xbp1^ΔIEC mice. These experiments reveal innate immune sensing of ER stress in IECs as an important mechanism of intestinal inflammation.

内质网（ER）压力通常在肠上皮细胞（IEC）中观察到，并且如果过度，则会引起自发性肠炎症，如IEC特异性X盒结合蛋白1（Xbp1）缺失的小鼠所显示的那样。与反应有关的转录因子。在这项研究中，XBP1缺失上皮（XBP1 ^ΔIEC）被证明可通过ER应激相关转录因子C / EBP同源性引起天然杀伤组2成员D（NKG2D）配体（NKG2DL）小鼠UL16结合蛋白（ULBP）样转录物1及其人类直系同源巨细胞病毒ULBP的表达增加蛋白质。小鼠IEC上NKG2DL表达的增加与上皮内表达NKG2D的第1组先天淋巴样细胞（ILCs； NK细胞或ILC1）的数量增加有关。NKG2D的阻滞作用在体外可抑制针对内质网应激的上皮细胞的细胞溶解作用，而在体内可抑制自发性肠炎。NK1.1的药理学消耗⁺细胞也显著改善肠炎，而肠炎中未改善重组酶激活基因1 ^{- / -} ; XBP1 ^ΔIEC老鼠。这些实验揭示了IEC中内质网应激的先天免疫感知是肠道炎症的重要机制。