Intestinal innate immunity by the IRE1-RIDD pathway

 描述（由申请人提供）：本项目的目标是了解肠道屏障上皮细胞的内质网（ER）如何运作， 感知微生物环境，以及这可能如何影响肠道免疫，宿主防御和炎症性肠病（IBD）的发病机制。肠上皮细胞对未折叠蛋白反应（UPR）和/或内质网（ER）应激的扰动高度敏感，这是一种基本的生物反应，起源于ER腔内正常发生的过程的改变。遗传研究已经揭示了几种ER应激/UPR相关基因作为IBD的风险因素，并且它们与肠道中宿主-微生物相互作用的改变以及关键促炎途径的激活相关。值得注意的是，IBD患者的肠上皮经常显示出ER应激的证据，暗示IBD中ER应激相关炎症的范例。我们最近发现了一种新的机制，即IRE 1a，三种哺乳动物ER压力传感器中最古老的一种，在先天免疫中充当模式识别分子，以感知从内腔环境进入ER的细菌和病毒蛋白（Cell Host Microbe，2013年5月）。以前，没有已知的先天免疫机制位于宿主细胞的ER（或高尔基体）中，尽管所有其他膜结合区室和胞质溶胶都配备有这样的因子。我们认为IRE 1通路可能是人类肠道先天免疫监视的一种普遍机制。例如，哺乳动物具有IRE 1的第二种同种型（IRE 1 β），其表达仅限于肠道的大量微生物定植上皮，并且其缺乏易患结肠炎。我们有初步的证据表明，IRE 1a在模式识别中可以像IRE 1a一样发挥作用;并且在先天免疫信号通路中具有增强的活性。我们假设IRE 1a或IRE 1a和IRE 1a两者可能起作用以感知肠道微生物菌群，从而以与健康和疾病相关的方式设定肠粘膜的免疫基调（或反应）。在这项资助中，我们将确定IRE 1作为肠上皮细胞中的模式识别分子的机制和功能，并阐明IRE 1信号通路感知肠道微生物菌群和影响粘膜免疫的生理后果。

 DESCRIPTION (provided by applicant): The goal of this project is to understand how the endoplasmic reticulum (ER) of barrier epithelial cells lining the intestine may operate to innately sense the microbial environment, and how this may impact gut immunity, host defense, and the pathogenesis of Inflammatory Bowel Disease (IBD). Intestinal epithelial cells are highly susceptible to perturbations in the Unfolded Protein Response (UPR) and/or Endoplasmic Reticulum (ER) stress, a fundamental biological response originating from an alteration of processes normally occurring within the ER lumen. Genetic studies have revealed several ER stress/UPR- associated genes as risk factors for IBD, and they are associated with alterations in host-microbe interactions in the intestine and with the activation of key proinflammatory pathways. Remarkably, the intestinal epithelium of IBD patients often shows evidence of ER stress, implicating a paradigm of ER stress-related inflammation in IBD. We recently discovered the novel mechanism that IRE1a, the most ancient of the three mammalian ER stress sensors, acts as a pattern-recognition molecule in innate immunity to sense bacterial and viral proteins entering the ER from the lumenal environment (Cell Host Microbe, May 2013). Previously, there were no known mechanisms of innate immunity located in the ER (or Golgi) of host cells, though all other membrane- bound compartments and the cytosol are equipped with such factors. We believe the IRE1 pathway may act as a generalized mechanism of innate immune surveillance in the human intestine. Mammals, for example, have a second isoform of IRE1 (IRE1ß) whose expression is restricted to the heavily microbial colonized epithelium of the gut, and whose absence predisposes to colitis. We have preliminary evidence that IRE1ß can act like IRE1a in pattern-recognition; and with enhanced activity in the innate immune signaling pathway. We hypothesize that IRE1ß, or both IRE1a and IRE1ß, may act to sense the gut microflora to set the immunologic tone (or response) of the intestinal mucosa in ways relevant to health and disease. In this grant, we will determine the mechanism and function of IRE1 as a pattern-recognition molecule in intestinal epithelial cells, and elucidate the physiologic consequence of the IRE1 signaling pathway for sensing the gut microflora and affecting mucosal immunity.