Programming of PMN host-defense function during transendothelial migration

PMN 跨内皮迁移过程中宿主防御功能的编程

• 批准号: 10666441
• 负责人: Yulia A Komarova
• 金额: $ 71.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-11 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666441
• 关键词: Address; Adherens Junction; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Calcium; Cells; Cues; Data; Diameter; Endothelium; Exhibits; Family member; Generations; Genes; Genetic Transcription; Goals; HIF1A gene; Health; Heterogeneity; Host Defense; Human; In Vitro; Infection; Inhalant dose form; Invaded; Ion Channel; Irritants; Knockout Mice; Lead; Leukocytes; Link; Lung; Lung infections; Lytic; Mediating; Membrane; Modeling; Molecular; NADPH Oxidase; Organelles; Oxidation-Reduction; Patients; Phagocytosis; Phagolysosome; Phagosomes; Phenotype; Piezo 1 ion channel; Play; Process; Property; Proteolysis; Pseudomonas aeruginosa pneumonia; Reactive Oxygen Species; Regulation; Research; Resolution; Role; Seminal; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; System; Testing; Therapeutic; Time; Tissues; Toxin; Up-Regulation; Vascular Endothelium; antimicrobial; cell killing; experience; experimental study; fighting; fungus; gain of function; genetic analysis; genetic approach; improved; in vivo; innate immune mechanisms; mechanical force; migration; mutant; neutrophil; pathogen; pharmacologic; pneumonia model; programs

PROJECT SUMMARY / ABSTRACT Polymorphonuclear neutrophil (PMN or neutrophil) maintain human health by rapidly eliminating the invading pathogens. These circulating cells transmigrate across the endothelial adherens junctions (AJs) to enter into the infected tissue and to clear the pathogens. Little is known about the role of mechanical forces which PMN experience during transmigration across the endothelium. Our Supporting Data describe the potentially important role of adherens junctions in activating PMN’s host defense function. We observed that activation of PMN-expressed Piezo1 during paracellular transmutation induced calcium influx, which in turn, promptly stabilized Hif1α and upregulated expression of NADPH oxidase 4 (Nox4) in PMN to program these cells to efficient “killers” of the pathogens. These findings have for the first time linked PMN-expressed Piezo1 to the host-defense function, leading to the fundamental question “how Ca2+ influx in PMN via Piezo1 program the host-defense function of PMN?” In Aim 1, we will determine the role of PMN-expressed Piezo1 signaling pathway in activating the host-defense function of transmigrating PMN. Here we will delineate the signaling pathways downstream of Piezo1 activation that promptly stabilizes Hif1α in PMN and programs PMN to become more efficient bacterial “killers”. The studies will involve genetic analysis of Piezo1- Hif1α signaling of the transmigrating PMN such as PMN-specific Piezo1 and Hif1α knockout mice. We will also determine whether pharmacological activation of Piezo1 or expression of gain-of-function Piezo1 mutant in PMN is sufficient to activate the PNM defense system in the relevant P. aeruginosa-induced pneumonia model. In Aim 2, we will determine the role of PMN-expressed Nox4 in regulating oxidative and lytic properties of PMN and in the efficient elimination of pathogens in lung. These studies will address the function of Nox4 in PMN in the mechanism of innate immune defense program. Using in vitro and in vivo experiments, we will determine how Hif1α induces activation of Nox4 gene and how Nox4 regulates oxidative and lytic properties of phagolysosome and efficient pathogen killing. The proposed studies will be essential for understanding the regulation of PMN host-defense function with the goal of identifying therapeutic potential of Piezo1 activators.

项目摘要 /摘要 多形核中性粒细胞（PMN或中性粒细胞）通过迅速消除入侵来维持人类健康 病原体。这些循环细胞在整个内皮粘附连接（AJS）中转移到 感染组织并清除病原体。关于PMN的机械力的作用知之甚少 在整个内皮传播过程中的经验。我们的支持数据描述了潜在的 粘附连接在激活PMN的宿主防御功能中的重要作用。我们观察到激活 副细胞变性期间PMN表达的压电1诱导钙影响，然后迅速迅速 在PMN中稳定HIF1α并更新了NADPH氧化管4（NOX4）的表达，以对这些细胞进行编程 病原体的有效“杀手”。这些发现首次将PMN表达的压电链接到 宿主防御功能，导致了一个基本问题：“ CA2+在PMN中如何通过PICZO进行影响 PMN的宿主防御功能？ 激活迁移PMN的宿主防御函数的途径。在这里，我们将描述信号 压电1激活下游的途径迅速稳定PMN中的HIF1α和PMN的程序 更有效的细菌“杀手”。研究将涉及对压电1-HIF1α信号传导的遗传分析 转移PMN，例如PMN特异性压电和HIF1α基因敲除小鼠。我们还将确定是否 PMN中压电1的药理激活或功能获得的压电突变体的表达足以 在相关的铜绿假单胞菌诱导的肺炎模型中激活PNM防御系统。在AIM 2中，我们将 确定PMN表达的NOX4在控制PMN的氧化和裂解特性中的作用 有效消除肺中的病原体。这些研究将解决NOX4在PMN中的功能 先天免疫防御计划的机制。使用体外和体内实验，我们将确定如何 HIF1α诱导Nox4基因的激活以及NOX4如何调节吞噬体的氧化和裂解特性 和有效的病原体杀害。拟议的研究对于理解PMN的调节至关重要 宿主防御功能的目的是识别压电1活化剂的治疗潜力。

项目成果

Mechanisms of increased endothelial permeability.

• DOI: 10.1139/y96-081
• 发表时间: 1996-07
• 期刊: Canadian journal of physiology and pharmacology
• 影响因子: 2.1
• 作者: Hazel Lum;A. Malik

Role of protein kinase Czeta in thrombin-induced RhoA activation and inter-endothelial gap formation of human dermal microvessel endothelial cell monolayers.

• DOI: 10.1016/j.mvr.2010.04.007
• 发表时间: 2010-09
• 期刊: Microvascular research
• 影响因子: 3.1
• 作者: Minshall RD;Vandenbroucke EE;Holinstat M;Place AT;Tiruppathi C;Vogel SM;van Nieuw Amerongen GP;Mehta D;Malik AB
• 通讯作者: Malik AB

Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury.

• DOI: 10.4049/jimmunol.0901808
• 发表时间: 2010-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Su X;Matthay MA;Malik AB
• 通讯作者: Malik AB

Size and dynamics of caveolae studied using nanoparticles in living endothelial cells.

• DOI: 10.1021/nn9012274
• 发表时间: 2009-12-22
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Wang, Zhenjia;Tiruppathi, Chinnaswamy;Minshall, Richard D.;Malik, Asrar B.
• 通讯作者: Malik, Asrar B.

Alveolar Stretch Activation of Endothelial Piezo1 Protects Adherens Junctions and Lung Vascular Barrier.

• DOI: 10.1165/rcmb.2019-0024oc
• 发表时间: 2020-01
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Ming Zhong;Wei Wu;Hojin Kang;Z. Hong;Shiqin Xiong;Xiao‐pei Gao;J. Rehman;Y. Komarova;A. Malik