Innate immune regulation of lung inflammation through mitochondrial dynamics

项目摘要 仅在美国，哮喘就影响了大约2400万人，其中600万是儿童， 18岁，每年造成3,000多人死亡1，2。一群免疫细胞，称为第2组 先天性淋巴样细胞（ILC 2）在驱动包括哮喘在内的肺部炎症性疾病中是不可或缺的， 2型细胞因子响应组织“警报”细胞因子信号的产生。尽管ILC 2取得了这些进展， 功能，我们对控制这种病理性的细胞内途径的知识存在根本性的空白。 在促炎ILC 2中的能力。在新的初步研究中，我们发现了一种新的联系， ILC 2线粒体结构形态和促炎能力的细胞内变化 导致肺部气道炎症。我们发现当暴露在肺组织中时 ILC 2增加线粒体质量并重塑其线粒体形态 网络从拉长的“融合”状态到碎片化的“裂变”状态。此外，我们还发现， 在木瓜蛋白酶过敏原暴露的小鼠模型中的裂变强烈地减少了ILC 2反应，并改变了它们的表达。 代谢编程，从而导致保护免受严重的肺部炎症。然而，尽管这些 进展，知识的根本差距仍然是关于1）如何重塑线粒体网络 形态学影响ILC 2-内源性气道炎症和2）通过 其线粒体动力学控制ILC 2促炎功能。在此，我提出两个目标， 细胞代谢和免疫生物学的尖端技术来剖析线粒体的作用， 在小鼠和哺乳动物中控制ILC 2代谢编程和病理功能的形态动力学 人类过敏性气道炎症。

PROJECT SUMMARY In the US alone, asthma affects approximately 24 million individuals, 6 million of whom are children under the age of 18, and is responsible for over 3,000 deaths annually1,2. A population of immune cells, called group 2 innate lymphoid cells (ILC2s), are integral in driving lung inflammatory diseases including asthma through production of type 2 cytokines in response to tissue `alarmin' cytokine signals. Despite these advances on ILC2 function, there is a fundamental gap in our knowledge of the intracellular pathways that control this pathologic capacity within pro-inflammatory ILC2s. In new preliminary studies, we uncovered a novel link between intracellular changes in the structural morphology of ILC2 mitochondria and the pro-inflammatory capacity within these cells that results in lung airway inflammation. We found that upon exposure to lung tissue inflammatory signals, ILC2s increased mitochondrial mass and remodeled their mitochondrial morphology network from a state of elongated `fusion' to fragmented `fission'. Furthermore, we found that inhibition of fission during a murine model of papain allergen exposure strongly curtailed ILC2 responses and altered their metabolic programming, thereby resulting in protection from severe lung inflammation. However, despite these advances, fundamental gaps in knowledge remain about 1) how remodeling of mitochondrial network morphology affects ILC2-intrinsic airway inflammation and 2) the identification of the metabolic mechanisms by which mitochondrial dynamics control ILC2 pro-inflammatory function. Here I propose two Aims consisting of cutting-edge techniques in cellular metabolism and immunobiology to dissect the role of mitochondrial morphology dynamics in controlling ILC2 metabolic programming and pathological function during murine and human allergic airway inflammation.