Neutrophil Survival and Demise During Inflammatory States

摘要 白介素1b是心血管疾病(CVD)中的一种促炎细胞因子，可导致生命危险 心血管事件，包括心肌梗塞和中风。白介素1a也会导致疾病。这个 控制IL-1a/b产生的细胞类型和信号通路仍有待全面评估。这 这项研究将调查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堆积是许多急慢性炎症性疾病的一个显著特征， 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 在生产和功能方面，我们缺乏对中性粒细胞谱系中细胞死亡信号的全面了解 在稳定状态下和在炎症期间。在冠心病患者中，中性粒细胞在 动脉粥样硬化斑块，并在容易破裂和斑块内出血的区域丰富。在……里面 冠状动脉疾病(CAD)小鼠模型，动脉粥样硬化斑块以中性粒细胞聚集为特征 在疾病的早期和晚期，中性粒细胞枯竭会损害单核细胞的早期募集 主动脉弓与动脉粥样硬化的进展。我们假设中性粒细胞在冠心病中释放IL-1 参与NLRP3炎症体、Caspase-8调节的细胞凋亡途径或MLKL调节的 坏死下垂途径。Bcl2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估，包括中性粒细胞祖细胞(NEP)、未成熟的中性粒细胞和 成熟的中性粒细胞。冠心病对人中性粒细胞系产生IL-1及细胞死亡信号的影响 将对细胞进行评估。这项研究将在冠状动脉疾病增加中识别有利于生存的信号 中性粒细胞寿命，以及控制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，以及炎性形式的细胞死亡。

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.