Determinants of human neutrophil fate after phagocytosis

吞噬作用后人类中性粒细胞命运的决定因素

• 批准号: 10328225
• 负责人: William M. Nauseef
• 金额: $ 48.68万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328225
• 关键词: Apoptosis; Apoptotic; Cell Death; Cells; Cessation of life; Complex; Cytoplasmic Granules; Disease; Environment; Failure; Generations; Health; Homeostasis; Host Defense; Human; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Innate Immune Response; Interleukin-1 beta; Invaded; Membrane; Microbe; Mission; NADPH Oxidase; Necrosis; Neisseria gonorrhoeae; Oxidants; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phase; Phosphotransferases; Production; Proliferating Cell Nuclear Antigen; Protein Kinase; Proteins; RIPK1 gene; Resolution; Role; Serine Protease; Signal Pathway; Signal Transduction; Staphylococcus aureus; System; Time; Tissues; cytokine; first responder; human pathogen; insight; macrophage; microbicide; neutrophil; novel; receptor; tool

Human innate immune response to microbes depends on the coordinated interactions among a variety of cells and secreted factors, with polymorphonuclear leukocytes (PMN) typically prominent among the first responders. In their capacity as phagocytic cells, PMN sequester ingested prey in membrane-bound phagosomes, where oxidants from the NADPH oxidase and proteins from granules synergize to create a toxic environment that promotes death and degradation of the engulfed microbe. In certain settings, a significant fraction of ingested microbes survives within PMN. The persistence of viable microbes within phagosomes not only provides a mechanism for sustained infection but also can modulate the local inflammatory tone by altering the programmed cell death of PMN and promoting PMN release of proinflammatory cytokines. Interference with phagocytosis-induced apoptosis of PMN (PICD), either by delaying apoptosis, as seen with N. gonorrhoeae (Ngc) or engaging a novel necrotic cell death pathway, as seen with Staphylococcus aureus (SA), thwarts resolution of the inflammatory response and causes release of host-derived danger signals that promote inflammation and secondary tissue damage. Thus, effective innate immune response requires not only death and degradation of invading microbes but also resolution of inflammation and reestablishment of homeostasis. The overarching hypothesis of this proposal is that the failure of PMN to undergo apoptotic cell death derails the resolution phase of the inflammatory response and instead amplifies disease. Because activated human PMN (hPMN) and their secreted products can sculpt the inflammatory tone in tissue, we propose to use Ngc and SA -- both human pathogens that survive within PMN, alter phagocytosis- induced cell fate pathways and elicit profound inflammatory local changes – as tools to probe mechanisms that dictate phagocyte fate and timely resolution of inflammation. We will pursue two Specific Aims: Aim 1: To determine the mechanisms that regulate human PMN fate . A. Determine the signaling pathways that differentially direct hPMN towards survival vs programmed cell death (apoptosis vs primary necrosis). B. Determine the composition and activities of the ripoptosome (intracellular complexes) in hPMN after phagocytosis C. Determine the role of Proliferating Cell Nuclear Antigen (PCNA) in the fate of phagocytosing hPMN Aim 2: To determine the mechanisms underlying hPMN secretion of IL-1β during phagocytosis A. Identify the role of inflammasomes in IL-1β production by hPMN during phagocytosis B. Determine the importance of serine proteases in generation of IL-1β C. Determine the role of Receptor-interacting kinase-3 (RIPK-3) in hPMN IL-1β secretion

人类对微生物的先天免疫反应依赖于多种微生物之间的协调相互作用。 细胞和分泌因子，其中多形核白细胞（PMN）通常在第一个细胞和分泌因子中突出。 响应者。作为吞噬细胞，中性粒细胞以膜结合的形式摄取猎物。 吞噬体，其中来自NADPH氧化酶的氧化剂和来自颗粒的蛋白质协同作用， 环境，促进死亡和降解的吞噬微生物。在某些情况下， 一部分摄入的微生物在PMN内存活。吞噬体中存活的微生物的持久性 不仅提供了持续感染的机制，而且还可以通过 改变PMN的程序性细胞死亡，促进PMN释放促炎细胞因子。 干扰吞噬诱导的中性粒细胞凋亡（PICD），无论是通过延迟凋亡，如与 N.淋病（Ngc）或参与一种新的坏死细胞死亡途径，如金黄色葡萄球菌 (SA)，阻碍炎症反应的消退，并导致宿主来源的危险信号的释放， 促进炎症和继发性组织损伤。因此，有效的先天免疫应答不需要 不仅可以杀死和降解入侵的微生物，还可以解决炎症和重建 体内平衡这个建议的首要假设是，PMN不能进行凋亡， 细胞死亡破坏炎症反应的消退阶段，反而放大疾病。 由于激活的人中性粒细胞（hPMN）及其分泌产物可以塑造炎症反应， 组织，我们建议使用Ngc和SA -这两种人类病原体在PMN中生存，改变吞噬作用， 诱导细胞命运途径，并引起深刻的炎症局部变化-作为探索机制的工具， 决定吞噬细胞的命运并及时解决炎症。我们将追求两个具体目标： 目标1：确定调节人类中性粒细胞命运的机制 . A.确定不同地指导hPMN存活与程序化的信号通路 细胞死亡（凋亡vs原发性坏死）。 B。测定hPMN中核糖体（胞内复合物）的组成和活性， 吞噬作用 C.确定增殖细胞核抗原（PCNA）在吞噬性hPMN命运中的作用 目的2：探讨人中性粒细胞（hPMN）在吞噬过程中分泌IL-1β的机制 A.炎性小体在hPMN吞噬过程中产生IL-1β中的作用 B。确定丝氨酸蛋白酶在IL-1β产生中的重要性 C.确定受体相互作用激酶-3（RIPK-3）在hPMN IL-1β分泌中的作用

项目成果

Spectroscopy of NOX Protein Family Members.

NOX 蛋白家族成员的光谱。

• DOI: 10.1007/978-1-4939-9424-3_7
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Nakano,Yoko;Nauseef,WilliamM
• 通讯作者: Nauseef,WilliamM