Consequences and significance of TAK1 inhibition in macrophages

巨噬细胞中 TAK1 抑制的后果和意义

• 批准号: 10434747
• 负责人: Wilfred Javier Lopez-Perez
• 金额: $ 1.37万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434747
• 关键词: Ablation; Apoptosis; Bacteria; Biological; Biology; CASP8 gene; Cell Death; Cells; Communicable Diseases; Epithelial Cells; Fibroblasts; Goals; Growth; Homeostasis; Host Defense; Host Defense Mechanism; Immune Targeting; Immune response; Inflammation; Inflammatory; Inflammatory Response; Invaded; Knock-out; Laboratories; Lead; MAP3K7 gene; Maintenance; Mediating; Mediator of activation protein; Membrane Potentials; Mitochondria; Modeling; Molecular; Morphology; Outcome; Parasites; Pathology; Pathway interactions; Phagocytes; Play; Prevention; Production; Protein Kinase; RIPK1 gene; Reactive Oxygen Species; Regulation; Respiration; Role; Signal Pathway; Signal Transduction; Structure; Tissues; Virus; base; cell type; insight; macrophage; microorganism; mitochondrial dysfunction; novel; pathogen; prevent; response

Macrophages are essential cells for tissue maintenance and mediating inflammation, and they reside ubiquitously throughout the body. Macrophages are primary phagocytic cells that engulf and destroy pathogens, parasites and any unwanted material. However, some pathogens actively invade macrophages to subvert and thwart macrophage defense. The pathogen-derived mechanisms to evade macrophage defense include disrupting the immune response. Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is a key intermediate molecule of the intracellular inflammatory signaling pathways, and is, therefore, one of the major targets of immune disruption by pathogens. It has been known that disruption of TAK1 not only blocks inflammatory signaling but also triggers activation of two types of cell death pathways, i.e. apoptosis and necroptosis. However, the biological significance of TAK1 inhibition-induced cell death pathways has been obscure. I found that inhibition of TAK1 activates these pathways and limits intracellular bacterial growth in macrophages. Most notably, it is associated with increases of mitochondrial reactive oxygen species (ROS). I hypothesize that mitochondrial ROS are a mediator of the macrophage defense against bacterial inhibition of TAK1. I aim to; i) characterize the effects of mitochondrial ROS induced by TAK1 inhibition on bacterial growth and mitochondrial homeostasis; ii) elucidate the mechanisms through which TAK1 regulates mitochondrial ROS. Outcomes of this project would yield novel understanding of TAK1 function, macrophage biology and host defense mechanisms.

巨噬细胞是组织维持和介导炎症的必需细胞，它们 遍布全身巨噬细胞是初级吞噬细胞， 消灭病原体、寄生虫和任何不需要的物质。然而，一些病原体主动侵入 巨噬细胞破坏和阻挠巨噬细胞防御。病原体衍生的机制， 逃避巨噬细胞防御包括破坏免疫反应。丝裂原活化蛋白 激酶激酶7（MAP 3 K7），也称为TAK 1，是一种关键的中间分子， 细胞内炎症信号通路，因此是免疫调节的主要靶点之一。 病原体的破坏。已经知道，TAK 1的破坏不仅可以阻断炎症反应， 信号转导，而且还触发两种类型的细胞死亡途径的激活，即细胞凋亡和 坏死性凋亡然而，TAK 1抑制诱导的细胞死亡途径的生物学意义已经被证实。 一直默默无闻。我发现抑制TAK 1可以激活这些通路， 巨噬细胞中的细菌生长。最值得注意的是，它与线粒体的增加有关。 活性氧（ROS）。我假设线粒体活性氧是一个调解人的 巨噬细胞防御细菌对TAK 1的抑制。我的目标是：i）描述 由TAK 1抑制细菌生长和线粒体稳态诱导的线粒体ROS; ii） 阐明TAK 1调节线粒体ROS的机制。这件事的结果 该项目将产生对TAK 1功能，巨噬细胞生物学和宿主防御的新理解 机制等