Resolving innate inflammatory responses to tissue injury and apoptotic cell clearance to develop novel therapeutic strategies for pulmonary diseases

炎症是身体对伤害、感染或疾病的反应。虽然有些疾病(例如肺炎和急性哮喘)会引起剧烈炎症，但它们有能力完全消退，而不会对周围组织造成残留损害。然而，在许多情况下，炎症可能会变得无序或失调，从而对身体组织造成额外的损害。事实上，炎症调节失调是全球疾病和健康不良的重大负担，特别是急性呼吸窘迫综合征、特发性肺纤维化、慢性支气管炎和新冠肺炎等肺部疾病。超过10亿人患有急性或慢性呼吸道疾病，尽管有巨大的疾病负担，经济生产力的损失，在许多情况下，过早死亡，但对于大多数这些疾病，药物治疗有限或没有有效的药物治疗。在过去20年的MRC支持下，我们研究了炎症如何消退，以及这些过程如何在慢性炎症条件下变得失调，目的是创造治疗这些疾病的新疗法。在这个令人兴奋的项目中，我们有两个主要目标。首先是了解炎症细胞用来从血流导航到炎症部位的机制。第二个是确定疾病期间产生的死亡细胞的摄入如何重新编程巨噬细胞，以推动炎症消退和完成组织修复过程。如果我们能确定参与这些过程的分子，这些分子就可以在治疗上有针对性地限制炎症细胞的招募，促进炎症的消退。为了实现这一点，我们使用了一种最简单的模式生物--常见的果蝇--来理解炎症细胞用来导航的“邮编”系统。使用苍蝇作为模型系统的一个主要好处是，它使我们能够实时观察活动物体内血细胞招募的过程，并通过基因筛查实验快速测试新的炎症靶点，这在哺乳动物中是不可能的。当我们确定了清除白细胞(中性粒细胞和巨噬细胞)用于导航到炎症伤口和清除不想要的死亡细胞的机制的新组件时，一个“突破”来了。在这个工作计划中，我们将研究这些新的途径，并使用临床相关的人类肺病模型(在小鼠中)来确定这些途径是否控制哺乳动物中的炎性细胞招募。对健康志愿者和肺部疾病患者的白细胞进行互补分析，将使我们能够在人类特有的疾病背景下检查这些途径。炎症消退的一个关键部分是清除被招募来对抗威胁/感染的炎性细胞。这一过程高度依赖于清道夫免疫细胞(巨噬细胞)，在不需要的炎症细胞经历了一种“沉默的自杀”后，巨噬细胞会吃掉并摧毁这些细胞。吞噬死亡的炎症细胞被认为是巨噬细胞完成组织修复过程的程序。然而，指导巨噬细胞执行这些功能的分子途径却知之甚少。了解这些途径可以让我们操纵它们，在慢性炎症中重新编程巨噬细胞。因此，再一次，我们将使用苍蝇强大的遗传学来深入和大规模地研究这些过程，然后使用小鼠模型来测试我们已经确定的候选对象，然后使用来自肺部疾病患者的白细胞进行检查。我们独特的跨物种协作方法将一支杰出的科学家团队聚集在一起，他们提供了一个机会，以前所未有的水平了解控制炎症的复杂机制。这些信息将对在可预见的未来为这些虚弱和不可治愈的疾病设计新的治疗方法至关重要。

Inflammation is the body's response to injury, infection or disease. While some conditions (e.g., pneumonia and acute asthma) cause dramatic inflammation, they have the capacity to resolve completely with no residual damage to surrounding tissues. However, in many cases inflammation can become disordered or dysregulated which causes additional damage to tissues of the body. In fact, dysregulated inflammation is responsible for a significant burden of global disease and ill health, especially lung diseases such as acute respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic bronchitis and COVID-19. Over 1 billion people suffer from acute or chronic respiratory diseases, and despite this huge burden of illness, loss of economic productivity and, in many cases, premature death, there is limited or no effective drug therapy for most of these conditions.With MRC support over the last 20 years, we have studied how inflammation resolves and how these processes become dysregulated in chronic inflammatory conditions with the goal of generating new therapies for treating these diseases. In this exciting project, we have two main aims. The first is to understand the machinery that inflammatory cells use to navigate from the bloodstream to the site of inflammation. The second is to determine how ingestion of dead cells generated during disease reprograms macrophages to drive inflammation resolution and complete the tissue repair process. If we can determine the molecules involved in these processes, these could be targeted therapeutically to limit recruitment of inflammatory cells and promote inflammation resolution. To achieve this, we have used one of the simplest model organisms, the common fruit fly, to understand the 'postcode' system used by inflammatory cells for navigation. A major benefit of using the fly as a model system is that it enables us to watch this process of blood cell recruitment in real time within a living animal and rapidly test for new inflammation targets through genetic screening experiments, something not possible in mammals. A 'breakthrough' came when we identified new components of the machinery that scavenger white blood cells (neutrophils and macrophages) use to navigate to inflammatory wounds and for the removal of unwanted dead cells. In this programme of work, we will investigate these novel pathways and use clinically relevant models of human lung disease (in mice) to determine if these pathways control inflammatory cell recruitment in mammals. Complementary analysis of white blood cells isolated from healthy volunteers and from patients with lung diseases will allow us to examine these pathways in human-specific disease contexts.A crucial part of inflammation resolution is the clearance of the inflammatory cells that have been recruited to combat the threat/infection. This process is highly dependent on scavenger immune cells (macrophages) which eat and destroy unwanted inflammatory cells after they have undergone a form of 'silent suicide'. Ingestion of dead inflammatory cells is thought to program macrophages to complete the tissue repair process. However, the molecular pathways that instruct macrophages to perform these functions are very poorly understood. Understanding these pathways could allow us to manipulate them to re-program macrophages in chronic inflammation. So, again, we will use the powerful genetics of the fly to investigate these processes in depth and at scale, then use mouse models to test the candidates we have identified before examining them using white blood cells from individuals with lung disease. Our unique cross-species collaborative approach brings together a team of outstanding scientists that offer an opportunity to understand, at an unprecedented level, the complex machinery controlling inflammation. This information will be critical to design novel therapies for these debilitating and untreatable diseases in the foreseeable future.