Project description
The role of macrophages in lung injury and repair
During inflammation or infection, circulating monocytes are recruited to the lung tissue, where they differentiate into macrophages (InfMoMac) and contribute to pathogen clearance, inflammation and repair. Lungs also contain resident macrophages which are involved in tissue homeostasis and immune regulation. Understanding how these different cell subsets function after lung injury is central for lung immunity. The ERC-funded MoMacTrajectALI project will map the trajectories and functional diversities of InfMoMac in mouse models of lung injury. Researchers will analyse how intrinsic and extrinsic signals influence InfMoMac subpopulations and study their interactions in mouse and human lungs. Project findings will provide the foundation for new therapies.
Objective
The lung is particularly exposed to airborne and blood-borne insults. The mechanisms underlying lung tissue repair are therefore of fundamental biological importance and have critical implications for the prevention life-threatening inflammatory and tissue-damaging responses. Lung-resident tissue macrophages and inflammatory monocyte-derived macrophages (InfMoMac) are key players in the maintenance of homeostasis, repair responses and disease pathogenesis. Yet, to date, the complexity of lung macrophage responses after injury is far from being resolved. Here, we propose to explore InfMoMac trajectories and functional diversity in an unprecedented manner. To this end, we will use mouse models of infectious and non-infectious lung injury combined with single cell and spatial analyses, robust fate-mapping models and gene targeting approaches to investigate the spatio-temporal regulation, the subtissular niches, the intrinsic molecular programs and the extrinsic stress-, inflammation- and niche-related signals imprinting the identities and functions of InfMoMac subpopulations, and the functional consequences of the maintenance of InfMoMac for lung immunity to a subsequent challenge. Finally, we will investigate the interactions of InfMoMac with niche cells in humans by analyzing the InfMoMac landscape in human injured lungs and by studying a novel human embryonic stem cell-derived lung organoid model in co-culture with monocyte-derived cells. Based on robust preliminary data, sophisticated models and cutting-edge technologies, this ambitious project will increase our understanding of the basic mechanisms underlying the fine-tuning of InfMoMac trajectories in response to lung injuries and will thus provide robust foundations to manipulate their fate in medically relevant conditions such as severe respiratory viral infections and acute respiratory distress syndrome.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
4000 Liege
Belgium