Endoplasmic reticulum stress and intestinal inflammation

内质网（ER）应激是一种古老的保守机制，它允许细胞，特别是那些具有重要分泌功能的细胞，如肠上皮细胞（IEC），通过一种称为未折叠蛋白反应（UPR）的机制来应对内质网内错误折叠或未折叠蛋白的出现。UPR由三个与er相关的通路组成，它们在细胞核内发出适应性转录程序的信号。最保守的途径是与肌醇需要酶1 （IRE1）相关的途径，IRE1通过核糖核酸内切酶和激酶活性分别调节X-box结合蛋白1 （XBP1）和Jun相关激酶（JNK）的转录活性。在IECs中特异性地缺失XBP1基因会导致自发性肠炎和对结肠炎诱导药物的敏感性，这与内质网络应激增加有关，Paneth和杯状细胞功能丧失，无法管理肠道微生物挑战以及IEC对细菌和免疫因子发出的信号过敏。因此，XBP1与IEC的功能影响IBD发病机制的两个主要决定因素；微生物群和对微生物群本身的免疫反应。考虑到内质网应激在炎症性肠病（IBD）和人类疾病的动物模型中很容易被证明，并且XBP1基因含有多态性，从而赋予IBD的发展风险，我们有理由提出，宿主在IEC内管理由环境因素（包括炎症本身）引起的内质网应激的能力是理解IBD发病机制的一个重要问题。目前的建议旨在：(1)通过表征三种主要UPR通路的活性、NFkB激活的作用、内质网应激和自噬通路之间的潜在交集，阐明内质网应激与上皮内XBP1功能不完全存在时发生的炎症之间的分子通路。XBP1缺乏对特定上皮亚型上皮细胞的影响，以及阻断NFkB或JNK是否可以改善XBP1相关炎症的测定；(2)通过定义TNFa的作用和xbp1缺陷小鼠肠道中肠道相关淋巴细胞群的特征，确定来自上皮的炎症介质参与炎症及其对粘膜免疫细胞群的影响；(3)通过表征XBP1缺失小鼠的微生物群，以及微生物群在诱导自发性肠炎和结肠炎易感性中的作用，明确XBP1缺失相关炎症加重或减轻的环境因素，并确定减轻内质酶应激的药物是否可以消除XBP1缺失上皮引起的肠道炎症。这些动物模型及其研究为确定和测试治疗和预防IBD的新治疗方法提供了一个独特的机会，这些方法通常可以扩展到具有广泛表型和遗传谱系的IBD患者。

DESCRIPTION (provided by applicant): Endoplasmic reticulum (ER) stress is an ancient conserved mechanism that allows cells, especially those with significant secretory function such as intestinal epithelial cells (IEC), to cope with the emergence of misfolded or unfolded proteins within the ER through a mechanism called the Unfolded Protein Response (UPR). The UPR consists of three ER-associated pathways that signal adaptive transcriptional programs within the nucleus. The most highly conserved pathway is that related to inositol requiring enzyme 1 (IRE1) which, through its endoribonuclease and kinase activities, regulates the transcriptional activity of X-box binding protein 1 (XBP1) and Jun related kinase (JNK), respectively. Deletion of the XBP1 gene specifically within IECs leads, uniquely, to spontaneous enteritis and sensitivity to colitis-inducing agents in association with increased ER stress, loss of Paneth and goblet cell function, an inability to manage luminal microbial challenges and a hypersensitivity of the IEC to signals emanating from bacterial and immune factors. XBP1 function with the IEC thus affects the two central determinants of IBD pathogenesis; the microbiota and immune response to the microbiota itself. Given that ER stress is readily demonstrable in animal models of inflammatory bowel disease (IBD) and the human condition and that the XBP1 gene harbors polymorphisms that confer risk for the development of IBD, it is reasonable to propose that the host's ability to manage ER stress within the IEC that is caused by environmental factors including inflammation itself is an important issue in understanding IBD pathogenesis. The current proposal aims to: (1) Elucidate the molecular pathways that connect unabated ER stress with inflammation that occurs in the presence of hypomorphic XBP1 function within the epithelium by characterizing the activity of the three major UPR pathways, the role NFkB activation, the potential intersection between ER stress and autophagy pathways, the effects of XBP1 deficiency on specific epithelial subtypes of epithelial cells and a determination of whether blockade of NFkB or JNK can ameliorate XBP1-related inflammation; (2) Define the inflammatory mediators derived from the epithelium that are involved in inflammation and their effects on mucosal immune cell populations by defining the role of TNFa and the characterization of the gut associated lymphoid cell populations in the intestines of XBP1-deficient mice, and; (3) Define the environmental factors involved in the exacerbation or alleviation of inflammation associated with XBP1- deficiency by characterizing the microbiome of XBP1-deficient mice and the role of the microbiota in inducing spontaneous enteritis and susceptibility to colitis and establishing whether agents that reduce ER stress can abrogate the intestinal inflammation arising from XBP1-deficient epithelia. These animal models and their interrogation provide a unique opportunity to identify and test novel therapeutic approaches for the treatment and prevention of IBD that may be generally extensible to IBD patients with a wide-range of phenotypic and genetic pedigrees. PUBLIC HEALTH RELEVANCE: XBP1 function within intestinal epithelial cells (IEC) is associated with endoplasmic reticulum (ER) stress and affects the two central determinants of inflammatory bowel disease (IBD) pathogenesis; the bacteria found in the gastro-intestinal tract and immune response to these bacteria itself. Given that ER stress is readily demonstrable in animal models of IBD and the human condition, and that the XBP1 gene harbors polymorphisms that confer risk for the development of IBD, we propose that the host's ability to manage ER stress within the IEC that is caused by environmental factors including inflammation itself is an important issue in understanding IBD pathogenesis. These animal models and their interrogation provide a unique opportunity to identify and test novel therapeutic approaches for the treatment and prevention of IBD that may be generally extensible to IBD patients with a wide-range of phenotypic and genetic pedigrees.