Intestinal innate immunity by the IRE1-RIDD pathway

 描述(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)如何先天运作 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)应激的扰动非常敏感，内质网(ER)应激是一种基本的生物学反应，源于内质网管腔内正常发生的过程的改变。遗传学研究表明，几个内质网应激/UPR相关基因是IBD的危险因素，它们与肠道宿主-微生物相互作用的改变和关键促炎途径的激活有关。值得注意的是，IBD患者的肠道上皮经常显示出ER应激的证据，这暗示了IBD中ER应激相关炎症的典范。我们最近发现了一种新的机制，即IRE1a是三种哺乳动物内质网应激传感器中最古老的，它在先天性免疫中作为模式识别分子，感知细菌和病毒蛋白从腔环境进入内质网(细胞宿主微生物，2013年5月)。以前，在宿主细胞的内质网(或高尔基体)中没有已知的天然免疫机制，尽管所有其他膜结合的隔室和胞浆都配备了这样的因子。我们认为IRE1途径可能是人类肠道天然免疫监视的一种普遍机制。例如，哺乳动物有第二种IRE1亚型(IRE1？)，其表达仅限于大量微生物定植的肠道上皮，缺乏该异构体易患结肠炎。我们有初步证据表明，IRE1？可以在模式识别中起到类似IRE1a的作用；并且在先天免疫信号通路中具有增强的活性。我们推测，IRE1？，或IRE1a和IRE1？？可能通过感知肠道微生物区系，以与健康和疾病相关的方式设定肠道粘膜的免疫基调(或反应)。在这项研究中，我们将确定IRE1在肠道上皮细胞中作为模式识别分子的机制和功能，并阐明IRE1信号通路在感知肠道微生物区系和影响粘膜免疫方面的生理后果。

 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.