Neutrophil lineage in inflammation

摘要 中性粒细胞构成了抵抗病原微生物的第一道细胞防线。为了回应亲- 炎症线索，不受限制的中性粒细胞活化诱导组织损伤。为了避免对环境造成有害影响， 宿主、嗜中性粒细胞数量、活化和寿命必须严格调节，但 在炎性疾病的情况下控制嗜中性粒细胞仍然是难以捉摸的。心血管疾病是主要的 全球死因。最近的证据支持中性粒细胞在冠状动脉粥样硬化的发展中的重要作用， 动脉疾病（CAD）。中性粒细胞存在于早期主动脉病变和易破裂的动脉粥样硬化中 血浆中性粒细胞分泌蛋白水平与CAD呈正相关， 建立，表明中性粒细胞胞吐介导CAD中的有害作用。此外，中性粒细胞 在动脉粥样硬化模型和新鉴定的中性粒细胞前体中， 现在已知它们可以介导炎症。中性粒细胞亚群如何促进CAD的疾病进展， 尚未研究，疾病中中性粒细胞多样性的调节也是未知的。炎性小体是 然而，NLRP 3炎性小体激活选择性地在动脉粥样硬化中的作用， 中性粒细胞在动脉粥样硬化形成中的作用尚未见报道， 在炎性小体活化和动脉粥样硬化形成的背景下的谱系细胞仍然未知。在这个协同 计划，项目1炎症和动脉粥样硬化过程中的中性粒细胞发育将研究中性粒细胞如何 异质性在患有CAD的人类受试者中被调节，以及中性粒细胞中NLRP 3炎性小体是如何被调节的。 动脉粥样硬化中祖细胞影响粒细胞生成和中性粒细胞异质性。项目2 Neurons 炎症和动脉粥样硬化过程中的机制将检验高脂血症与动脉粥样硬化之间的差异 调节CAD中中性粒细胞前体的囊泡运输和相关功能，建立机制 NLRP 3诱导的中性粒细胞胞吐失调，并实施翻译方法以减少 中性粒细胞炎症。项目3炎症状态下的神经元存活和消亡 表征中性粒细胞中NLRP 3炎性体组分的表达和功能 谱系，并将定义高血压诱导的炎症的影响和死亡受体的作用 IL-1β产生中的信号传导、中性粒细胞谱系细胞活力中的线粒体凋亡和坏死性凋亡 动脉粥样硬化形成中的信号传导。我们的协同和独特的计划使用三个互补的专业知识 著名研究人员，中性粒细胞发育，中性粒细胞胞内功能调节等领域的专家 和炎症，以研究中性粒细胞祖细胞的不受限制的激活和成熟的中心假设， 中性粒细胞是心血管疾病的基本过程。这些研究将导致新的方法， 治疗CAD中的嗜中性粒细胞介导的炎症。

ABSTRACT Neutrophils constitute the first line of cellular defense against pathogenic microorganisms. In response to pro- inflammatory cues, unrestricted neutrophil activation induces tissue damage. To avoid deleterious effects to the host, neutrophil numbers, activation, and lifespan must be tightly regulated, but the molecular mechanisms that control neutrophils in the context of inflammatory disease remain elusive. Cardiovascular disease is the leading global cause of death. Recent evidence supports an important role for neutrophils in the development of coronary artery disease (CAD). Neutrophils are present in early aortic lesions and in rupture-prone atherosclerotic plaques, and a positive correlation between plasma levels of neutrophil secretory proteins and CAD has been established, suggesting that neutrophil exocytosis mediates detrimental effects in CAD. Furthermore, neutrophil production is increased in the bone marrow in atherosclerotic models and newly identified neutrophil precursors are now known to mediate inflammation. How neutrophil subsets contribute to disease progression in CAD has not been studied and the regulation of neutrophil diversity in disease is unknown. The inflammasome is an emerging driver in atherosclerosis; however, the role of the NLRP3 inflammasome activation selectively in neutrophils on atherogenesis has not been studied and the mechanisms regulating the functions of neutrophil lineage cells in the context of inflammasome activation and atherogenesis remain unknown. In this synergistic program, Project 1 Neutrophil Development During Inflammation and Atherosclerosis will study how neutrophil heterogeneity is modulated in human subjects with CAD, and how the NLRP3 inflammasome in neutrophil progenitors influences granulopoiesis and neutrophil heterogeneity in atherosclerosis. Project 2 Neutrophil Mechanisms During Inflammation and Atherosclerosis will test the hypothesis that hyperlipidemia differentially regulates vesicular trafficking and associated functions of neutrophil precursors in CAD, establish mechanisms of NLRP3-induced neutrophil exocytosis dysregulation and implement translational approaches to decrease neutrophil inflammation in CAD. Project 3 Neutrophil Survival and Demise During Inflammatory States will characterize the expression and function of components of the NLRP3 inflammasome in cells of the neutrophil lineage, and will define the effects of hyperlipidemia-induced inflammation and the roles of death receptor signaling in IL-1β production, mitochondrial apoptosis in viability of neutrophil lineage cells, and necroptosis signaling in atherogenesis. Our synergistic and unique program uses the complementary expertise of three renown researchers, experts in the areas of neutrophil development, neutrophil intracellular function regulation and inflammation, to study the central hypothesis that unrestricted activation of neutrophil progenitors and mature neutrophils is a fundamental process in cardiovascular disease. These studies will lead to novel approaches to treat neutrophil-mediated inflammation in CAD.