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Neutrophil Development During Inflammation and Atherosclerosis

炎症和动脉粥样硬化期间中性粒细胞的发育

基本信息

批准号：
10651786
负责人：
Catherine C Hedrick
金额：
$ 70.11万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2021-08-16 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651786
关键词：
Acceleration Acute Age Antigen-Antibody Complex Apolipoprotein E Atherosclerosis Blood Bone Marrow Bone Marrow Stem Cell Cardiovascular Diseases Cell Death Cells Cholesterol Chronic Disease Clinical Clinical Data Coronary Coronary Angiography Cytometry Data Development Disease Elastases Event Exocytosis Frequencies Generations Glucose Granulopoiesis Heterogeneity Histone H3 Human Hyperlipidemia Immunity Individual Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-6 Knockout Mice Link Lipids Lytic Macrophage Malignant Neoplasms Measures Molecular Mus Myocardial Pathway interactions Patients Pattern Peroxidases Phenotype Plasma Predisposition Production Reporting Role Severity of illness Signal Transduction Testing Tissues Virginia acute infection atherogenesis atheroprotective cytokine extracellular fighting medically necessary care mouse model myocardial injury neutrophil novel therapeutic intervention oxidized low density lipoprotein pathogen peripheral blood progenitor secretory protein sensor sex stem cells tumor

项目摘要

PROJECT SUMMARY Neutrophils acutely respond to inflammatory signals in tissues and play a role in cardiovascular disease (CAD). After activation by cholesterol and oxidized low density lipoproteins, neutrophils produce cytokines, degranulate to release myeloperoxidase, azurocidin, and elastase, generate neutrophil extracellular traps (NETs), and trigger lytic cell death. Neutrophils are produced in the bone marrow by stem cell progenitors and, once mature, egress to blood and tissues to fight inflammation. We recently discovered an early committed neutrophil progenitor stem cell (NeP) present in human and mouse bone marrow. Here, we present new data demonstrating the presence of NeP in the peripheral blood of mice and humans with CAD, suggesting that NeP modulate granulopoiesis and inflammation outside of the bone marrow. In this project, we will focus on inflammation via activation of the Nlrp3 inflammasome, as we find that Nlrp3 and ll1b are highly expressed in NeP. Activation of the inflammasome sensor Nlrp3 triggers a robust inflammatory response, including IL-1β production. In Project 1, we hypothesize that activation of the Nlrp3 inflammasome within NeP triggers granulopoiesis and neutrophil heterogeneity which promotes atherosclerosis progression. We will test our hypothesis by studying inflammasome activation in both mice and humans with cardiovascular disease (CAD). In Specific Aim 1 we will test how neutrophil subsets are phenotypically and functionally changed in human CAD patients compared to healthy subjects. These subjects are undergoing medically necessary coronary angiography as part of the ongoing Coronary Assessment in Virginia (CAVA) study, and their extent of atherosclerosis is measured clinically. We will analyze NeP, neutrophil heterogeneity, and the role of the neutrophilic Nlrp3 inflammasome in blood of these subjects and link these findings to clinical parameters. In Specific Aim 2 we will use atherosclerotic mouse models to test how intrinsic action of the Nlrp3 inflammasome in neutrophils impacts granulopoiesis and atherosclerosis. We will use mixed chimeric mouse models with Nlrp3-/-, Gsdmd-/-, and Gsdme-/- mice to assess how inflammasome pathways in NeP regulate granulopoiesis. New neutrophil-specific and macrophage-specific Nlrp3 knock-out mice crossed to atherosclerosis-susceptible, apolipoprotein E-deficient (apoE-/-) mice will be used to directly compare how action of neutrophil vs macrophage Nlrp3 inflammasomes impact neutrophil heterogeneity and atherosclerosis. We will use a new mouse model to assess Nlrp3 action in NeP versus mature neutrophils on atherosclerosis. We will define how Nlrp3 inflammasome activation in neutrophil progenitors impacts granulopoiesis and atherosclerosis, which in turn could lead to new therapeutic approaches targeting Nlrp3 components in neutrophils for atherosclerosis and other inflammatory diseases.

项目概要中性粒细胞对组织中的炎症信号做出敏锐的反应，并在心血管疾病中发挥作用（CAD）。中性粒细胞被胆固醇和氧化低密度脂蛋白激活后产生细胞因子，脱粒释放髓过氧化物酶、azurocidin 和弹性蛋白酶，产生中性粒细胞胞外陷阱（NET），并引发裂解细胞死亡。中性粒细胞由干细胞祖细胞在骨髓中产生一旦成熟，就会进入血液和组织以对抗炎症。我们最近发现了一个早期的人类和小鼠骨髓中存在定型中性粒细胞祖干细胞 (NeP)。在这里，我们最新数据证明 NeP 存在于小鼠和人类的外周血中 CAD，表明 NeP 调节骨髓外的粒细胞生成和炎症。在这个项目中，我们将通过激活 Nlrp3 炎症小体来关注炎症，因为我们发现 Nlrp3 和 ll1b 在 NeP 中高度表达。炎症小体传感器 Nlrp3 的激活会触发强大的炎症反应，包括 IL-1β 的产生。在项目 1 中，我们假设激活 NeP 内的 Nlrp3 炎性体触发粒细胞生成和中性粒细胞异质性，促进动脉粥样硬化的进展。我们将通过研究炎症小体来检验我们的假设在患有心血管疾病（CAD）的小鼠和人类中均被激活。在具体目标 1 中，我们将测试人类 CAD 患者中性粒细胞亚群的表型和功能如何变化与健康受试者相比。这些受试者正在接受医学上必要的冠状动脉治疗血管造影作为弗吉尼亚州正在进行的冠状动脉评估 (CAVA) 研究的一部分，及其范围动脉粥样硬化是通过临床测量的。我们将分析 NeP、中性粒细胞异质性以及这些受试者血液中存在中性粒细胞 Nlrp3 炎性体，并将这些发现与临床参数联系起来。在具体目标 2 中，我们将使用动脉粥样硬化小鼠模型来测试 Nlrp3 的内在作用中性粒细胞中的炎症小体影响粒细胞生成和动脉粥样硬化。我们将使用混合使用 Nlrp3-/-、Gsdmd-/- 和 Gsdme-/- 小鼠的嵌合小鼠模型来评估炎症小体通路如何 NeP 调节粒细胞生成。新型中性粒细胞特异性和巨噬细胞特异性 Nlrp3 敲除小鼠与动脉粥样硬化易感、载脂蛋白 E 缺陷 (apoE-/-) 小鼠杂交，将用于直接比较中性粒细胞与巨噬细胞 Nlrp3 炎症小体的作用如何影响中性粒细胞异质性和动脉粥样硬化。我们将使用新的小鼠模型来评估 Nlrp3 在 NeP 与成熟小鼠中的作用中性粒细胞对动脉粥样硬化的影响。我们将定义 Nlrp3 炎症小体如何在中性粒细胞祖细胞中激活影响粒细胞生成和动脉粥样硬化，进而可能导致新的治疗方法靶向中性粒细胞中的 Nlrp3 成分，治疗动脉粥样硬化和其他炎症性疾病。