A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages

脓毒症免疫抑制的新机制:单核细胞和巨噬细胞的耗竭

基本信息

  • 批准号:
    10020416
  • 负责人:
  • 金额:
    $ 37.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-20 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Sepsis is a life-threatening condition that affects more than 1 million patients a year in the United States. Growing evidence indicates that immunosuppression is a major driving force for mortality in sepsis. Macrophages play essential roles in immune response to pathogens. Previous clinical studies have shown that peripheral monocytes are depleted in septic patients through apoptosis. Recent in vitro studies revealed that bacterial components, flagellin, the rod protein of the type III secretion system (T3SS), or LPS induce pyroptosis of macrophages through activation of inflammasome pathways. In this proposal, we provide convincing evidence that both peripheral monocytes and tissue macrophages are depleted due to pyroptosis in mouse sepsis models including the cecal ligation and puncture (CLP) model. We show that intravenous injection of flagellin or the rod proteins induced depletion of peripheral monocytes and macrophages in tissues. We further demonstrate that depletion of these cells in mice impaired immune response and increased mortality rate by subsequent challenged with E. coli. Importantly, our data indicate that tissue factor released from pyroptotic monocytes and macrophages triggers disseminated intravascular coagulation (DIC). Thus, our findings identified monocyte/macrophage depletion as a novel mechanism of immunosuppression and DIC in sepsis. The goal of this application is to delineate the underlying mechanisms of monocyte/macrophage depletion and its contribution to immunosuppression in sepsis. Aim 1 is to delineate the mechanisms of pyroptotic monocyte and macrophage death during sepsis. The working hypothesis is that inflammasome activation and subsequent pyroptosis play a critical role in monocyte/macrophage depletion during sepsis. Mouse models deficient in caspase-1, caspase-11, caspase-1/11 double, or GSDMD (whole-body and macrophage-specific) will be used to elucidate the detailed mechanism of inflammasome activation and pyroptosis in monocyte/macrophage depletion. Aim 2 is to identify the mechanism by which rod protein and flagellin induce pyroptosis leading to monocyte/macrophage depletion. We recently identified an intracellular binding partner of EprJ, the acyl-CoA dehydrogenase family member type 9 (ACAD9) in macrophages. We will use different approaches to test the hypothesis that the ACAD9-dependent pathway contributes to macrophage depletion. Aim 3 is to identify the contribution of monocyte/macrophage depletion to immunosuppression during sepsis. We will use a combination of sepsis models to investigate the role of monocyte/macrophage depletion in immunosuppression during sepsis. Peripheral monocyte depletion in septic patients will also be investigated. Completion of the proposed studies will reveal a novel molecular mechanism of immunosuppression induced by Gram-negative bacteria. Such findings will significantly advance our understanding about the pathogenesis of sepsis and identify new drug targets for this deadly disease.
败血症是一种危及生命的疾病,在美国每年有超过100万患者受到影响。

项目成果

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ZHENYU Li其他文献

ZHENYU Li的其他文献

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{{ truncateString('ZHENYU Li', 18)}}的其他基金

Inflammasome Activation Triggers Systemic Coagulation in Sepsis
脓毒症中炎症小体激活引发全身凝血
  • 批准号:
    10645452
  • 财政年份:
    2022
  • 资助金额:
    $ 37.73万
  • 项目类别:
A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages
脓毒症免疫抑制的新机制:单核细胞和巨噬细胞的耗竭
  • 批准号:
    10436162
  • 财政年份:
    2019
  • 资助金额:
    $ 37.73万
  • 项目类别:
A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages
脓毒症免疫抑制的新机制:单核细胞和巨噬细胞的耗竭
  • 批准号:
    10194546
  • 财政年份:
    2019
  • 资助金额:
    $ 37.73万
  • 项目类别:
A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages
脓毒症免疫抑制的新机制:单核细胞和巨噬细胞的耗竭
  • 批准号:
    10605060
  • 财政年份:
    2019
  • 资助金额:
    $ 37.73万
  • 项目类别:
Crosstalk between membrane traffic proteins and integrin activation
膜运输蛋白和整合素激活之间的串扰
  • 批准号:
    8837170
  • 财政年份:
    2014
  • 资助金额:
    $ 37.73万
  • 项目类别:
PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS
肥胖引起的血小板激活促进动脉粥样硬化性血管事件
  • 批准号:
    8360249
  • 财政年份:
    2011
  • 资助金额:
    $ 37.73万
  • 项目类别:
PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS
肥胖引起的血小板激活促进动脉粥样硬化性血管事件
  • 批准号:
    8174559
  • 财政年份:
    2010
  • 资助金额:
    $ 37.73万
  • 项目类别:
PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS
肥胖引起的血小板激活促进动脉粥样硬化性血管事件
  • 批准号:
    7960386
  • 财政年份:
    2009
  • 资助金额:
    $ 37.73万
  • 项目类别:

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