Resolving innate inflammatory responses to tissue injury and apoptotic cell clearance to develop novel therapeutic strategies for pulmonary diseases
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Inflammation Research
Abstract
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.
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.
Technical Summary
Dysregulated inflammation, frequently observed in respiratory disease, causes an enormous burden of worldwide ill health and premature death. Understanding mechanisms of immune cell recruitment to injured tissue and subsequent clearance of apoptotic cells affords a unique opportunity to identify novel targets to treat acute and chronic lung disease. Using the synergistic expertise of the applicants, we will leverage the powerful genetics and live imaging potential of the fruit fly Drosophila melanogaster married to mechanistic studies in vertebrate (zebrafish) and mammalian (mouse and human) systems. This approach will screen for, identify and dissect the molecular machinery that drives immune cell migration and mechanisms of apoptotic cell reprogramming of macrophages.
Core project deliverables:
1. Examine mechanisms of immune cell wound recruitment in Drosophila, and identify novel inflammation regulating genes for further study in mammalian systems.
2. Determine if PTPN21 and MEGF11, recently identified via our Drosophila studies, represent evolutionarily conserved damage sensing and migration machinery in mammalian immune cells and their impact upon experimental lung injury.
3. Determine how sensing and uptake of dying (apoptotic) cells reprogrammes macrophage behaviour to influence their fate and function using Drosophila, mouse and human systems.
4. Use these platforms to dissect the functionality of novel targets identified from parallel CRISPR/Cas genome wide screens and transcriptomic analyses on immune cells responding to tissue injury or apoptotic cells.
5. Translate our findings made in the fly, mouse and healthy human cells into severe pulmonary inflammation (as typified by acute respiratory distress syndrome) using established pipelines and tissue biobanks.
Together, these approaches will identify and test evolutionarily conserved regulators of inflammation to find much needed novel targets to treat inflammatory diseases.
Core project deliverables:
1. Examine mechanisms of immune cell wound recruitment in Drosophila, and identify novel inflammation regulating genes for further study in mammalian systems.
2. Determine if PTPN21 and MEGF11, recently identified via our Drosophila studies, represent evolutionarily conserved damage sensing and migration machinery in mammalian immune cells and their impact upon experimental lung injury.
3. Determine how sensing and uptake of dying (apoptotic) cells reprogrammes macrophage behaviour to influence their fate and function using Drosophila, mouse and human systems.
4. Use these platforms to dissect the functionality of novel targets identified from parallel CRISPR/Cas genome wide screens and transcriptomic analyses on immune cells responding to tissue injury or apoptotic cells.
5. Translate our findings made in the fly, mouse and healthy human cells into severe pulmonary inflammation (as typified by acute respiratory distress syndrome) using established pipelines and tissue biobanks.
Together, these approaches will identify and test evolutionarily conserved regulators of inflammation to find much needed novel targets to treat inflammatory diseases.
