Pro- and anti-inflammatory immune mechanisms and alterations of the intestinal stem cell niche as a result of endoplasmic reticulum stress in intestinal epithelial cells
Final Report Abstract
Intestinal epithelial cells (IECs) are continuously confronted with microbes and other environmental stimuli that are challenging for this highly secretory cell type and lead to endoplasmic reticulum (ER) stress, which is resolved by activation of compensatory signaling pathways, together called the unfolded protein response (UPR). ER stress is commonly detected in IECs under homeostatic conditions and increased in inflammatory bowel disease (IBD). When ER stress is unresolved, as observed in mice with IEC-restricted deletion of the UPR effector molecule X box binding protein-1 (XBP1), spontaneous enteritis develops, indicating a critical role of ER stress in shaping the intestinal inflammatory tone. The objective of this project was to characterize pro- and anti-inflammatory immune responses that are triggered by IEC ER stress. We were able to demonstrate that IEC ER stress induces the expression of the natural killer group 2 member D (NKG2D) ligand mouse UL16-binding protein-like transcript 1 (MULT1) via the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP). Increased expression of NKG2D ligands by IECs is associated with intraepithelial accumulation of NKG2D-expressing group 1 innate lymphoid cells (ILCs). Blockade of NKG2D or depletion of NK1.1-positive cells reduces ER stress–induced enteritis whereas the absence of adaptive immune cells does not ameliorate inflammation. These experiments suggest that group 1 ILCs sense IEC ER stress via NKG2D and elicit a pro-inflammatory response. We were further able to show that IEC ER stress plays a previously unexpected role in intestinal homeostasis by orchestrating an immunoglobulin A (IgA) response that is protective against ER stress–induced enteric inflammation. In this pathway, IEC ER stress is signaled to the peritoneal cavity by an unknown transmissible factor and causes T cell- and microbiotaindependent expansion and activation of peritoneal B1b cells, which migrate to the intestine and give rise to plasma cells producing polyclonal and polyreactive IgA. Similarly, human subjects homozygous for the ER stress–inducing variant of autophagy-related protein 16-1 (ATG16L1) exhibit increased numbers of small intestinal IgA-positive cells compared with controls. Thus, IEC ER stress can trigger a beneficial “eustress” response that antagonizes its pro-inflammatory function and may play a role in IBD.
Publications
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Intestinal Epithelial Cell Endoplasmic Reticulum Stress Promotes MULT1 Up-Regulation and NKG2D-Mediated Inflammation. The Journal of Experimental Medicine, 214(10), pp.2985–2997
Shuhei Hosomi, Joep Grootjans, Markus Tschurtschenthaler, Niklas Krupka, Juan D. Matute, Magdalena B. Flak, Eduardo Martinez-Naves, Manuel Gomez del Moral, Jonathan N. Glickman, Mizuki Ohira, Lewis L. Lanier, Arthur Kaser, Richard S. Blumberg
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Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Science, 363(6430), pp.993–998
Joep Grootjans, Niklas Krupka, Shuhei Hosomi, Juan D. Matute, Svetlana Saveljeva, Thomas Gensollen, Jarom Heijmans, Thomas Hanley, Hai Li, Julien P. Limenitakis, Stephanie C. Ganal-Vonarburg, Shengbao Suo, Adrienne M. Luoma, Yosuke Shimodaira, David Q. Shih, Margaret E. Conner, Jonathan N. Glickman, Gwenny M. Fuhler, Noah W. Palm, Marcel R. de Zoete, C. Janneke van der Woude, Guo-Cheng Yuan, Kai W. Wucherpfennig, Stephan R. Targan, Philip Rosenstiel, Richard A. Flavell, Kathy D. McCoy, Andrew J. Macpherson, Arthur Kaser, Richard S. Blumberg
