Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Dig Dis. 2012;30(4):341-6. doi: 10.1159/000338121. Epub 2012 Jul 12.
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.
内质网（ER）应激是由于内质网中错误折叠或未折叠蛋白质的存在而引起的基本生物学反应，称为未折叠蛋白反应（UPR）。UPR 由三个主要的近端效应器协调，其中 IRE1/XBP1 途径代表最保守的进化途径。由于其高分泌负担，肠道上皮细胞极易受到 UPR 的干扰，这已通过功能研究如缺乏 Xbp1 表达的小鼠（特别是在肠道上皮细胞中）所揭示。遗传研究揭示了几种 ER 应激/UPR 相关基因，包括 XBP1、ORMDL3、AGR2 和 MUC19 作为 IBD 的风险因素，并且已经描述了 XBP1 的特定功能、罕见变体。Xbp1(Δ)(IEC) 小鼠自发发展为小肠结肠炎，伴有隐窝脓肿，类似于人类 IBD，而 Agr2(-/-) 小鼠发展为肉芽肿性回肠炎。对 Xbp1(Δ)(IEC) 小鼠的机制研究表明，其对 Paneth 细胞有重大影响，与肠道中宿主-微生物相互作用的改变有关，并且宿主中关键促炎途径的激活与未解决的 ER 应激和低功能 Xbp1 功能直接相关。值得注意的是，IBD 患者的肠道上皮细胞通常表现出明显的 ER 应激证据，这不能轻易归因于这些遗传风险因素，这表明 ER 应激相关炎症的范式可能既是 IBD 中肠道炎症的主要起源，也是其强有力的维持者。
