The pathogenic roles of GSDMD-dependent gut epithelium extracellular vesicles in IBD

GSDMD依赖性肠上皮细胞外囊泡在IBD中的致病作用

基本信息

批准号：
10211603
负责人：
Theresa Torres Pizarro
金额：
$ 42.05万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-08 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10211603
关键词：
Address Affect Anti-Tumor Necrosis Factor Therapy Area Binding Proteins Biogenesis Biological Response Modifiers Biopsy CDC37 gene Caspase Cells Cellular Stress Chronic Clinical Colitis Colon Communications Media Complex Data Detection Disease Environment Environmental Risk Factor Epithelial Epithelial Cells Etiology Family Family member Granulocyte-Macrophage Colony-Stimulating Factor Human Immune Immune response Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interferon Type II Interferons Interleukin-1 Interleukin-18 Intestinal Content Knockout Mice Length Lipid Binding Lytic Mediating Modeling Molecular Molecular Chaperones Mucous Membrane Mus N-terminal Nonlytic Organoids Pathogenesis Pathogenicity Pathway interactions Patients Play Polyubiquitination Preventive measure Production Proteomics Resistance Role Signal Transduction Source Specimen Stimulus Surface T-Cell Activation T-Lymphocyte TNF gene Testing Therapeutic Tissues Treatment Failure United States Vesicle adaptive immune response autocrine base cytokine dextran sulfate sodium induced colitis exosome extracellular vesicles gastrointestinal epithelium inflammatory disease of the intestine injured insight intestinal epithelium macrophage member mouse model novel pre-clinical research public health relevance recruit response success ubiquitin-protein ligase

项目摘要

Abstract Understanding how environmental factors trigger dysregulated immune responses was identified as a key challenge in preclinical research for the pathogenesis of inflammatory bowel disease (IBD). Dysregulated responses to the luminal environment by intestinal epithelial cells (IECs) have been widely postulated to be a driver of IBD. On the other hand, the success of immunomodulatory biologics, such as vedolizumab and ustekinumab, clearly demonstrate the central role of T cells, especially pathogenic T cells, in IBD. However, it remains unclear how IECs convey innate immune detection at mucosal surfaces to adaptive immune responses and subsequent inflammation. Emerging at the center of this sensing function is the inflammasome, which can detect cellular stress and danger signals, such as ATP, found in injured tissues during chronic inflammation. In our quest to understand the role of the inflammasome in IECs, we found that IECs release large amounts of small extracellular vesicles (sEVs) containing polyubiquitinated IL-1 family cytokines, including IL-1 and IL-18, in response to inflammasome activation in a GSDMD-dependent manner. Importantly, IEC-derived sEVs represent a novel form of communication between IECs and T cells. In particular, IL-18 promotes inflammatory pathogenic T cells via induction of IFN? and GM-CSF production. sEVs-derived from inflamed mouse colons exacerbate disease and confer resistance to anti-TNF treatment in a T cell transfer colitis model. Consistently, IECs from biopsies of inflamed areas from IBD patients displayed enhanced capacity to produce sEVs compared to that from non-inflamed areas. Thus, we hypothesize that IEC-derived sEVs play a critical role in IBD pathogenesis by amplifying epithelial inflammatory responses and promoting pathogenic T cells via the release of sEVs containing IL-1 family cytokines, including IL-1 and IL-18, and perhaps IL-33. This application seeks to determine the molecular mechanism(s) that underlie the release of sEVs and assess the importance of sEVs in promoting pathogenic T cells and anti-TNF therapy failure in murine models of colitis and in patient-derived specimens from IBD patients.

抽象的了解环境因素如何引发免疫反应失调被认为是炎症性肠病 (IBD) 发病机制临床前研究的一个关键挑战。肠上皮细胞 (IEC) 对管腔环境的失调反应被广泛认为是 IBD 的驱动因素。另一方面，维多珠单抗和优特克单抗等免疫调节生物制剂的成功清楚地证明了 T 细胞，尤其是致病性 T 细胞在 IBD 中的核心作用。然而，目前尚不清楚 IEC 如何将粘膜表面的先天免疫检测传递给适应性免疫反应和随后的炎症。这种传感功能的核心是炎症小体，它可以检测慢性炎症期间受损组织中发现的细胞应激和危险信号，例如 ATP。在我们探索炎症小体在 IEC 中的作用的过程中，我们发现 IEC 释放大量含有多泛素化 IL-1 家族细胞因子（包括 IL-1 和 IL-18）的小细胞外囊泡 (sEV)，以响应炎症小体的激活依赖于 GSDMD 的方式。重要的是，IEC 衍生的 sEV 代表了 IEC 和 T 细胞之间的一种新型通信形式。特别是，IL-18 通过诱导 IFN? 促进炎症致病性 T 细胞的产生。和 GM-CSF 生产。在 T 细胞转移结肠炎模型中，源自发炎小鼠结肠的 sEV 会加剧疾病并赋予抗 TNF 治疗耐药性。一致的是，与非发炎区域相比，IBD 患者发炎区域活检中的 IEC 表现出产生 sEV 的能力增强。因此，我们假设 IEC 衍生的 sEV 在 IBD 发病机制中发挥着关键作用，通过释放含有 IL-1 家族细胞因子（包括 IL-1 和 IL-18，也许还有 IL）的 sEV，放大上皮炎症反应并促进致病性 T 细胞。 -33。本申请旨在确定 sEV 释放的分子机制，并评估 sEV 在结肠炎小鼠模型和来自 IBD 患者的患者标本中促进致病性 T 细胞和抗 TNF 治疗失败的重要性。