Consequences and significance of TAK1 inhibition in macrophages

巨噬细胞是组织维持和调节炎症的必要细胞，它们 无处不在地存在于全身。巨噬细胞是主要的吞噬细胞，吞噬和 销毁病原体、寄生虫和任何不需要的材料。然而，一些病原体会主动入侵 巨噬细胞颠覆和挫败巨噬细胞防御。病原体衍生的机制 逃避巨噬细胞防御包括扰乱免疫反应。丝裂原激活蛋白 激酶7(MAP3K7)，也被称为TAK1，是一种关键的中间分子。 细胞内炎症信号通路，因此是免疫的主要靶点之一 病原体的破坏。已经知道，TAK1的破坏不仅可以阻断炎症性 但也触发了两种类型的细胞死亡途径的激活，即细胞凋亡和 坏死性下垂。然而，TAK1抑制诱导的细胞死亡通路的生物学意义 一直默默无闻。我发现抑制TAK1激活了这些通路，并限制了细胞内 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)。我推测线粒体ROS是一种 巨噬细胞防御细菌对TAK1的抑制。我的目标是；i)描述…的影响 TAK1抑制细菌生长和线粒体内稳态诱导的线粒体ROS； 阐明TAK1调控线粒体ROS的机制。这样做的结果是 该项目将对TAK1的功能、巨噬细胞生物学和宿主防御产生新的理解 机械装置。

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.