Endoplasmic Reticulum Stress and Inflammation

Endoplasmic reticulum (ER) stress due to the presence of misfolded or unfolded proteins in the ER invokes a fundamental biological response, termed the unfolded protein response (UPR). The UPR is orchestrated by three main proximal effectors, of which the IRE1/XBP1 pathway represents the evolutionarily most conserved one. Due to its high secretory burden, the intestinal epithelium is highly susceptible to perturbations in the UPR as has been revealed by functional investigations such as in mice that lack Xbp1 expression, specifically in the intestinal epithelial cells. Genetic studies have revealed several ER stress/UPR-associated genes, including XBP1, ORMDL3, AGR2 and MUC19 as risk factors for IBD, and specific functional, rare variants have been described for XBP1. Xbp1(Δ)(IEC) mice spontaneously develop small intestinal enteritis with crypt abscesses reminiscent of human IBD, while Agr2(-/-) mice develop granulomatous ileocolitis. Mechanistic studies into Xbp1(Δ)(IEC) mice revealed a major effect on Paneth cells associated with alterations in host-microbe interactions in the intestine, and the activation of key proinflammatory pathways in the host directly associated with unresolved ER stress and hypomorphic Xbp1 function. Remarkably, the intestinal epithelium of IBD patients commonly exhibits evidence of marked ER stress, which cannot easily be attributed to these genetic risk factors alone and indicates that the paradigm of ER stress-related inflammation might be both a primary originator as well as a potent perpetuator of intestinal inflammation in IBD.