Neutrophil Survival and Demise During Inflammatory States

炎症状态下中性粒细胞的存活和死亡

• 批准号: 10651795
• 负责人: HAROLD M HOFFMAN
• 金额: $ 61.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 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/10651795
• 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 Membrane Permeability; Cell Survival; Cells; Cessation of life; Collaborations; Compensation; Coronary Arteriosclerosis; Data; Dependence; Disease; Dominant-Negative Mutation; Event; Family member; Flagellin; Generations; Genetic Models; Hemorrhage; Human; Impairment; Induction of Apoptosis; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukins; Kinetics; LDL Cholesterol Lipoproteins; Life; Ligation; Longevity; Lytic; MCL1 gene; Macrophage; 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; antagonist; aortic arch; automated image analysis; cell type; chronic inflammatory disease; cytokine; experimental study; extracellular; gain of function mutation; live cell imaging; loss of function; mitochondrial membrane; monocyte; mouse model; neglect; neutrophil; novel; oxidized low density lipoprotein; progenitor; receptor; recruit; response

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.

摘要 白细胞介素-1b是心血管疾病（CVD）中的促炎细胞因子，可导致危及生命的 心血管事件，包括心肌梗死和中风。白细胞介素-1a也有助于疾病。的 控制IL-1 a/B产生的细胞类型和信号通路仍有待全面评估。这 本研究将研究心血管疾病中的中性粒细胞谱系及其在IL-1 a/B产生中的作用。 组织中的神经元积聚是许多急性和慢性炎性疾病的标志性特征， 包括冠心病。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，我们缺乏对中性粒细胞系细胞死亡信号的全面了解 在稳定状态和炎症期间。在冠状动脉疾病患者中， 动脉粥样硬化斑块，并在易于破裂和斑块内出血的区域富集。在 冠状动脉疾病（CAD）的小鼠模型，动脉粥样硬化斑块以中性粒细胞的积累为特征 在疾病的早期和晚期，中性粒细胞耗竭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。我们假设冠心病患者中性粒细胞通过 参与NLRP 3炎性体，半胱天冬酶-8调节的凋亡途径，或MLKL调节的凋亡途径。 坏死性凋亡途径Bcl-2家族成员对Caspase-8依赖的细胞凋亡和IL-1释放的调控 将在中性粒细胞谱系细胞中进行评价，包括中性粒细胞祖细胞（NeP）、未成熟中性粒细胞和 成熟中性粒细胞冠心病对人中性粒细胞系IL-1产生及细胞死亡信号的影响 将对细胞进行评估。这项研究将确定冠状动脉疾病中的促生存信号， 中性粒细胞寿命，和控制IL-1产生的促死亡信号，中性粒细胞胞外陷阱的形成， 线粒体的释放和细胞死亡的炎性形式。