Neutrophil Survival and Demise During Inflammatory States

炎症状态下中性粒细胞的存活和死亡

基本信息

批准号：
10270899
负责人：
HAROLD M HOFFMAN
金额：
$ 64.29万
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/10270899
关键词：
Ablation Acute Alleles Animal Model Apoptosis Apoptotic Area Arterial Fatty Streak Atherosclerosis Automobile Driving BCL2 gene CASP8 gene CD95 Antigens Cardiac Cardiovascular Diseases Cardiovascular system Cell Death Cell Death Signaling Process Cell Lineage Cell Survival Cells Cessation of life Collaborations Coronary Arteriosclerosis Crystallization Data Dependence Disease Dominant-Negative Mutation Event Family member Flagellin Generations Genetic Models Hemorrhage Human Impairment Inflammasome Inflammation Inflammatory Interleukin-1 Interleukins Kinetics LDL Cholesterol Lipoproteins Life Ligation Longevity Lytic MCL1 gene Mediating Mitochondria Morphology Mus Myelogenous Myocardial Infarction Outer Mitochondrial Membrane Pathogenicity Pathway interactions Patients Pharmacology Study Production Proteins Regulation Reporting Research Role Rupture Signal Pathway Signal Transduction Stimulus Stroke Swelling Tissues Tumor Necrosis Factor Receptor Work aortic arch automated image analysis cell type chronic inflammatory disease cytokine experimental study extracellular gain of function mutation live cell imaging loss of function macrophage mitochondrial membrane monocyte mouse model neglect neutrophil novel oxidized low density lipoprotein progenitor receptor recruit response

项目摘要

Abstract Interleukin-1b is a pro-inflammatory cytokine in cardiovascular disease (CVD) contributing to life-threatening cardiovascular events including myocardial infarction and stroke. Interleukin-1a also contributes to disease. The cell types and signaling pathways that control IL-1a/b production remains to be comprehensively evaluated. This study will investigate the neutrophil lineage in cardiovascular disease and their role in IL-1a/b production. Neutrophil accumulation in tissues is a hallmark feature of many acute and chronic inflammatory diseases, including coronary artery disease. Despite our broad understanding of the factors controlling neutrophil production and function, we lack a comprehensive understanding of cell death signaling in the neutrophil lineage at steady state and during inflammation. In patients with coronary artery disease, neutrophils accumulate in atherosclerotic plaques, and are enriched in areas that are prone to rupture and intraplaque hemorrhage. In mouse models of coronary artery disease (CAD), atherosclerotic plaques feature an accumulation of neutrophils in early and advanced stages of disease, and neutrophil depletion impairs the early recruitment of monocytes to the aortic arch and the progression of atherosclerosis. We hypothesize that neutrophils release IL-1 in CAD by engaging the NLRP3 inflammasome, the Caspase-8-regulated apoptosis pathway, or the MLKL-regulated necroptotic pathway. The control of Caspase-8-dependent apoptosis and IL-1 release by Bcl-2 family members will be evaluated in neutrophil lineage cells including neutrophil progenitors (NePs), immature neutrophils, and mature neutrophils. The effects of CAD on IL-1 production and cell death signaling in human neutrophil lineage cells will be assessed. This research will identify pro-survival signals in coronary artery disease increasing neutrophil longevity, and pro-death signals that control IL-1 production, formation of neutrophil extracellular traps, release of mitochondria, and inflammatory forms of cell death.

抽象的白介素1b是心血管疾病（CVD）的促炎细胞因子，导致威胁生命心血管事件，包括心肌梗塞和中风。白介素-1a也有助于疾病。这控制IL-1A/B产生的细胞类型和信号通路尚待全面评估。这研究将研究心血管疾病中的中性粒细胞谱系及其在IL-1A/B产生中的作用。中性粒细胞在组织中的积累是许多急性和慢性炎症性疾病的标志性特征，包括冠状动脉疾病。尽管我们对控制中性粒细胞的因素有广泛的了解生产和功能，我们对中性粒细胞谱系中细胞死亡信号的传导缺乏全面的了解在稳定状态和炎症期间。在冠状动脉疾病的患者中，中性粒细胞积累动脉粥样硬化的斑块，并在容易破裂和内部出血的区域富集。在冠状动脉疾病的小鼠模型（CAD），动脉粥样硬化斑块具有嗜中性粒细胞的积累在疾病的早期和晚期阶段，中性粒细胞的耗竭会损害单核细胞的早期募集主动脉弓和动脉粥样硬化的进展。我们假设中性粒细胞在CAD中释放IL-1 参与NLRP3炎性体，caspase-8调节的凋亡途径或MLKL调节坏死途径。 Bcl-2家族成员对caspase-8依赖性细胞凋亡和IL-1释放的控制将在包括嗜中性粒细胞祖细胞（NEP），未成熟嗜中性粒细胞和成熟的中性粒细胞。 CAD对人类中性粒细胞谱系IL-1产生和细胞死亡信号传导的影响将评估细胞。这项研究将确定增加冠状动脉疾病中的生存信号中性粒细胞的寿命和控制IL-1产生的促疾病信号，中性粒细胞外陷阱的形成，线粒体的释放和细胞死亡的炎症形式。