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2011 ; 140
(6
): 1738-47
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Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial
function in inflammatory bowel disease
#MMPMID21530740
Kaser A
; Blumberg RS
Gastroenterology
2011[May]; 140
(6
): 1738-47
PMID21530740
show ga
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-?B 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.