title: Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease.
abstract: Increasing evidence has emerged that supports an important intersection between 3 fundamental cell biologic pathways in the pathogenesis of inflammatory bowel disease. These include the intersection between autophagy, as revealed by the original identification of ATG16L1 and IRGM as major genetic risk factors for Crohn's disease, and intracellular bacterial sensing, as shown by the importance of NOD2 in autophagy induction upon bacterial entry into the cell. A pathway closely linked to autophagy and innate immunity is the unfolded protein response, initiated by endoplasmic reticulum stress due to the accumulation of misfolded proteins, which is genetically related to ulcerative colitis and Crohn's disease (XBP1 and ORMDL3). Hypomorphic ATG16L1, NOD2, and X box binding protein-1 possess the common attribute of profoundly affecting Paneth cells, specialized epithelial cells at the bottom of intestinal crypts involved in antimicrobial function. Together with their functional juxtaposition in the environmentally exposed intestinal epithelial cell, their remarkable functional convergence on Paneth cells and their behavior in response to environmental factors, including microbes, these 3 pathways are of increasing importance to understanding the pathogenesis of inflammatory bowel disease. Moreover, in conjunction with studies that model deficient nuclear factor-κB function, these studies suggest a central role for altered intestinal epithelial cell function as one of the earliest events in the development of inflammatory bowel disease.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D001343:Autophagy; D001419:Bacteria / Q000276:immunology; D004721:Endoplasmic Reticulum; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000382:microbiology / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000503:physiopathology*; D007422:Intestines / Q000276:immunology* / Q000382:microbiology*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D013312:Stress, Physiological; D056811:Unfolded Protein Response
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein