Macrophage Plasticity in Inflammatory Lung Injury

项目研究摘要/摘要 治疗急性肺损伤下的高炎性状态的根本挑战 呼吸窘迫障碍(ALI/ARDS)是广泛的抗炎干预可能损害宿主 并可能加剧引发ALI/ARDS的潜在感染过程。有针对性的小说 因此，治疗ALI/ARDS的方法需要深入了解复杂的炎症机制 减轻损伤程度，促进炎症消退，启动肺修复 而不会影响主机防御。现已认识到，肺内巨噬细胞(M-φ)代表多种 多功能细胞群。它们有感知病原体和危险信号的能力，以及它们的可塑性 多样性使它们能够以专门的方式对特定的利基环境做出反应。他们能够 通过激活专门的转录程序，以变色龙的方式改变它们的表型。因此， 它们具有显著的放大炎症和协调肺部炎症消退的能力。 肺损伤和恢复动态平衡。Mφ通过释放一系列细胞因子来执行这些功能， 吞噬微生物，吞噬死亡细胞，并提供必要的炎症或修复 向附近的手机发出信号。该计划的中心重点将是准确定义不同的角色 巨噬细胞亚群在炎症性肺损伤中的作用及其信号转导机制 巨噬细胞，从而带来肺损伤的解决。项目1将检验两个假设 特异性离子通道，P2RX7(嘌呤能受体2亚型X7)和钾(K+)外流通道 TWIK2调节可塑性以促进肺损伤或激活修复程序。项目2将测试 认为转录因子CREB及其下游靶标是反转录因子的关键调节因子的假设 肺泡Mφ的炎症和修复功能。项目3将测试内皮细胞衬里 所有肺血管均通过调节Mφ中的Wnt信号来调控Mφ的可塑性。项目4将测试 炎症时循环CX3CR1+单核细胞补充肺间质M-φ的假说 并可指导肺组织损伤修复方案。这四个项目由以下机构支持和补充 高度创新的科学核心，将提供重要的光遗传工具(合成生物学和 光遗传学核心B)、超分辨率和活体成像(高级成像核心C)，以及访问 临床样本以及巨噬细胞的单细胞转录分析(临床样本和 基因组学核心D)揭开肺损伤中巨噬细胞生物学的复杂性，从而为 ALI/ARDS亟需新的治疗方法。

RESEARCH SUMMARY/ABSTRACT OF PROGRAM The fundamental challenge in treating the hyper-inflammatory state underlying Acute Lung Injury/Acute Respiratory Distress Disorder (ALI/ARDS) is that broad anti-inflammatory interventions could compromise host defense and potentially exacerbate the underlying infectious process that triggered ALI/ARDS. Novel targeted approaches to treat ALI/ARDS thus require an in-depth understanding of the intricate inflammatory mechanisms to reduce the extent of injury and promote the resolution of inflammation as well as the initiation of lung repair without compromising host defense. It is now recognized that macrophages (Mφ) in lungs represent diverse multi-functional cell populations. They have the ability to sense pathogens and danger signals, and their plasticity and diversity allows them to respond in specialized manners to specific niche environments. They are able to change their phenotypes in a chameleon-like manner by activation of specialized transcriptional programs. Thus, they have the remarkable ability to amplify inflammation and also to coordinate resolution of lung inflammatory lung injury and restore homeostasis. Mφ carry out these functions through the release of an array of cytokines, phagocytosis of microbes, efferocytosis of dead cells, and provide the essential inflammatory or reparative signals to nearby cells. The central focus of this program will be to precisely define the roles of distinct macrophage subpopulations in inflammatory lung injury and signaling nodes to harness the plasticity of macrophages and thereby bring about the resolution of lung injury. Project 1 will test the hypothesis that two specific specific ion channels, P2RX7 (Purinergic Receptor 2 subtype X7) and the potassium (K+) efflux channel TWIK2 regulate the plasticity to either promote lung injury or to activate the repair program. Project 2 will test the hypothesis that the transcription factor CREB and its downstream targets are critical regulators of the anti- inflammatory and reparative function of alveolar Mφ. Project 3 will test the hypothesis that endothelial cells lining all lung vessels direct the plasticity of Mφ via modulation of Wnt signaling in Mφ. Project 4 will test the hypothesis that circulating postnatal CX3CR1+ monocytes replenish lung interstitial Mφ during inflammatory injury and can direct the lung tissue repair program. These four Projects are supported and complemented by highly innovative scientific Cores which will provide important optogenetic tools (Synthetic Biology and Optogenetics Core B), super-resolution and intravital imaging (Advanced Imaging Core C), and access to clinical samples as well as single cell transcriptomic analysis of macrophages (Clinical Sampling and Genomics Core D) to unravel the complexities of macrophage biology in lung injury, thus paving the way for much-needed novel therapeutic approaches in ALI/ARDS.