Endoplasmic reticulum stress and intestinal inflammation

描述(申请人提供)：内质网(ER)应激是一种古老的保守机制，允许细胞，特别是那些具有显著分泌功能的细胞，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中错误折叠或未折叠蛋白质的出现。UPR由三个ER相关通路组成，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，该途径通过其内切核酸酶和激酶活性分别调节X-box结合蛋白1(XBP1)和Jun相关蛋白(JNK)的转录活性。IECS中特有的XBP1基因缺失会导致自发性肠炎和对结肠炎诱导剂的敏感性，并与内质网应激增加、Paneth和杯状细胞功能丧失、无法应对腔微生物挑战以及IEC对细菌和免疫因素发出的信号高度敏感相关。因此，XBP1与IEC的功能会影响IBD发病的两个核心决定因素：微生物区系和对微生物区系本身的免疫反应。鉴于内质网应激在炎症性肠病(IBD)动物模型和人类状况中很容易被证明，并且XBP1基因含有增加IBD发生风险的多态性，有理由认为宿主管理由包括炎症本身在内的环境因素引起的IEC内ER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)通过表征三个主要的UPR通路的活性、NFkB的激活作用、ER应激和自噬通路的潜在交叉点、XBP1缺乏对特定上皮细胞亚型的影响以及阻断NFkB或JNK是否可以改善XBP1相关的炎症，阐明未减弱的内质网应激与上皮内XBP1功能低下时发生的炎症的分子通路；(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，定义参与炎症反应的上皮炎性介质及其对粘膜免疫细胞群的影响，以及(3)通过描述XBP1缺陷小鼠的微生物群的特征，以及微生物区系在诱导自发性肠炎和结肠炎易感性方面的作用，定义参与加剧或缓解XBP1缺陷相关炎症的环境因素，并确定降低ER应激的药物是否可以消除XBP1缺陷上皮引起的肠道炎症。这些动物模型及其询问为识别和测试治疗和预防IBD的新的治疗方法提供了一个独特的机会，这些方法通常可以推广到具有广泛表型和遗传家系的IBD患者。 公共卫生相关性：肠上皮细胞(IEC)内的XBP1功能与内质网(ER)应激有关，并影响炎症性肠病(IBD)发病的两个核心决定因素；胃肠道中发现的细菌和对这些细菌本身的免疫反应。鉴于内质网应激在IBD动物模型和人类条件下很容易被证明，并且XBP1基因含有增加IBD发生风险的多态，我们认为宿主在IEC内管理由包括炎症本身在内的环境因素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。这些动物模型及其询问为识别和测试治疗和预防IBD的新的治疗方法提供了一个独特的机会，这些方法通常可以推广到具有广泛表型和遗传家系的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.