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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：
ZHENYU Li
金额：
$ 37.73万
依托单位：
UNIVERSITY OF KENTUCKY
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

来源：
https://reporter.nih.gov/project-details/10020416
关键词：
Affect Apoptosis B-Lymphocytes Bacteria Binding CASP1 gene Caspase Cell Death Cell membrane Cells Cessation of life Cleaved cell Clinical Research Data Dendritic Cells Disease Disseminated Intravascular Coagulation Effector Cell Escherichia coli Family member Flagellin Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Immune Immune response Immunosuppression Impairment In Vitro Infection Inflammasome Inflammatory Lead Life Modeling Molecular Morbidity - disease rate Mus N-terminal Pathogenesis Pathway interactions Patients Peripheral Phagocytosis Play Proteins Reporting Research Project Grants Rod Role Rupture Sepsis T-Cell Depletion Testing Thromboplastin Tissues Type III Secretion System Pathway United States Work acyl-CoA dehydrogenase cecal ligation puncture driving force insight intravenous injection macrophage monocyte mortality mouse model new therapeutic target novel pathogen release factor response septic patients

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。