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：
10470240
负责人：
Catherine C Hedrick
金额：
$ 70.28万
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/10470240
关键词：
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 Lead Link Lipids Lytic Malignant Neoplasms Measures Molecular Mus Myocardial Pathway interactions Patients Peroxidases Phenotype Plasma Play Production Reporting Role Severity of illness Signal Transduction Testing Tissues Virginia acute infection atherogenesis atheroprotective cytokine extracellular fighting macrophage 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.

项目摘要中性粒细胞对组织中的炎症信号敏锐反应，并在心血管疾病中发挥作用（CAD）。胆固醇和氧化的低密度脂蛋白激活后，中性粒细胞产生细胞因子，脱粒以释放髓过氧化物酶，azurocidin和弹性蛋白酶产生嗜中性粒细胞外陷阱（网），并触发裂解细胞死亡。中性粒细胞是由干细胞祖细胞在骨髓中产生的而且，一旦成熟，就会流出血液和组织以抵抗炎症。我们最近发现了一个早期人和小鼠骨髓中存在的实用中性粒细胞祖细胞（NEP）。在这里，我们目前的新数据表明，NEP在小鼠和人类的外周血中存在 CAD，表明NEP在骨髓外调节颗粒和炎症。在这个项目，我们将通过激活NLRP3炎症体来关注炎症，因为我们发现NLRP3和 LL1B在NEP中高度表达。激活炎性体传感器NLRP3触发了强大的炎症反应，包括IL-1β产生。在项目1中，我们假设激活 NEP内的NLRP3炎症体会触发粒状和中性粒细胞异质性促进动脉粥样硬化进展。我们将通过研究炎症体来检验我们的假设患有心血管疾病（CAD）的小鼠和人类的激活。在特定目标1中，我们将测试人CAD患者的中性粒细胞子集在表型和功能上如何改变与健康受试者相比。这些受试者正在接受医学上必要的冠状动脉血管造影是弗吉尼亚州正在进行的冠状动脉评估（CAVA）研究的一部分，其范围动脉粥样硬化是在临床上测量的。我们将分析NEP，中性粒细胞异质性和这些受试者血液中的中性粒细胞NLRP3炎症体，并将这些发现与临床参数联系起来。在特定目标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体会影响颗粒状和动脉粥样硬化。我们将使用混合带有NLRP3的嵌合小鼠模型 - / - ，GSDMD - / - 和GSDME - / - 小鼠如何评估炎性途径的方式在NEP中调节颗粒。新的中性粒细胞特异性和巨噬细胞特异性的NLRP3敲除小鼠交叉到动脉粥样硬化的启发性，载脂蛋白E缺陷型（APOE - / - ）将直接用于直接比较中性粒细胞与巨噬细胞NLRP3炎症的作用如何影响中性粒细胞异质性和动脉粥样硬化。我们将使用新的鼠标模型评估NEP与成熟的NLRP3动作中性粒细胞在动脉粥样硬化上。我们将定义中性粒细胞祖细胞中的NLRP3炎性体激活影响粒状和动脉粥样硬化，这反过来可能导致新的治疗方法针对中性粒细胞中的NLRP3成分，用于动脉粥样硬化和其他炎症性疾病。