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

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.
摘要 了解环境因素如何触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关键挑战。肠上皮细胞(IEC)对管腔环境的失调反应已被广泛认为是IBD的驱动因素。另一方面,免疫调节生物制剂(如Vedolizumab和乌司奴单抗)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应答和随后的炎症。在这种传感功能的中心出现的是炎性小体,它可以检测细胞压力和危险信号,如ATP,在慢性炎症期间在受损组织中发现。在我们寻求了解炎性小体在IEC中的作用时,我们发现IEC以GSDMD依赖性方式响应炎性小体激活而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)。重要的是,IEC衍生的sEV代表了IEC和T细胞之间的一种新的通讯形式。特别是,IL-18促进炎症致病性T细胞通过诱导IFN?和GM-CSF生产。来源于发炎小鼠结肠的sEV在T细胞转移结肠炎模型中加重疾病并赋予对抗TNF治疗的抗性。一致地,来自IBD患者的炎症区域的活检的IEC与来自非炎症区域的IEC相比显示出增强的产生sEV的能力。因此,我们假设IEC衍生的sEV通过释放含有IL-1家族细胞因子(包括IL-1和IL-18,可能还有IL-33)的sEV,放大上皮炎症反应并促进致病性T细胞,在IBD发病机制中发挥关键作用。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IBD患者来源的标本中促进致病性T细胞和抗TNF治疗失败的重要性。

项目成果

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Theresa Torres Pizarro其他文献

Theresa Torres Pizarro的其他文献

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{{ truncateString('Theresa Torres Pizarro', 18)}}的其他基金

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
  • 批准号:
    10853519
  • 财政年份:
    2023
  • 资助金额:
    $ 42.05万
  • 项目类别:
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
  • 批准号:
    10386894
  • 财政年份:
    2021
  • 资助金额:
    $ 42.05万
  • 项目类别:
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
  • 批准号:
    10599251
  • 财政年份:
    2021
  • 资助金额:
    $ 42.05万
  • 项目类别:
GSDMD-dependent IL-1 signaling in intestinal inflammation
肠道炎症中 GSDMD 依赖性 IL-1 信号传导
  • 批准号:
    10654589
  • 财政年份:
    2020
  • 资助金额:
    $ 42.05万
  • 项目类别:
GSDMD-dependent IL-1 signaling in intestinal inflammation
肠道炎症中 GSDMD 依赖性 IL-1 信号传导
  • 批准号:
    10223160
  • 财政年份:
    2020
  • 资助金额:
    $ 42.05万
  • 项目类别:
GSDMD-dependent IL-1 signaling in intestinal inflammation
肠道炎症中 GSDMD 依赖性 IL-1 信号传导
  • 批准号:
    10441357
  • 财政年份:
    2020
  • 资助金额:
    $ 42.05万
  • 项目类别:
Histology/Imaging Core C
组织学/成像核心 C
  • 批准号:
    10555242
  • 财政年份:
    2015
  • 资助金额:
    $ 42.05万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10555238
  • 财政年份:
    2015
  • 资助金额:
    $ 42.05万
  • 项目类别:
Histology/Imaging Core C
组织学/成像核心 C
  • 批准号:
    10361545
  • 财政年份:
    2015
  • 资助金额:
    $ 42.05万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10361543
  • 财政年份:
    2015
  • 资助金额:
    $ 42.05万
  • 项目类别:

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