Macrophage diversity: nature vs. nurture

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Macrophages are long-lived immune cells that provide the first line of defense against the non-self. They also serve as local and systemic signaling hubs coordinating tissue homeostasis and function. Furthermore, macrophages are major actors in diseases as diverse as cancer and neurodegeneration, with context-dependent beneficial or detrimental effects. These cells represent therefore powerful therapeutic targets but their diversity, which likely contributes to their different action in pathological conditions, remains a major and yet poorly understood feature. Defining the relative impact of plasticity and adaptation vs. lineage specificity on macrophage function hence represents a major challenge in fundamental and medical science. Therefore, identification of molecular checkpoints during macrophage diversification, depending on their ontogeny and tissue environment but also on the encountered challenges, might allow macrophage modulation and resetting during disease. Here, we plan to dissect the bases and the impact of diversity of invertebrate and vertebrate macrophages across development and adulthood by combining lineage tracing, transcriptomics (bulk/single cell resolution) and functional assays, as well as genetic and pharmacological manipulations. Hence, we identified three specific aims we will focus on during this project. First, we will define whether macrophage heterogeneity reflects different cell states or identities. Next, we will evaluate the differences between macrophage subpopulations issued from distinct hematopoietic wave and in a final aim, we will assess the impact of short-term and long-term challenges on macrophage plasticity in flies and compare with results obtained in mice. To this purpose, we will exploit the complementary expertise of the French team (A. Giangrande) on fly macrophage diversity, epigenetics and development and that of the German team (K. Kierdorf) on fly and mouse macrophage physiology and tissue specification. We will also interact with the teams of J. Shim (Seoul) and T. Mukherjee (Bangalore), who share interest in metabolic and transcriptional macrophage signatures. Given the evolutionary conservation of the major biological processes from flies to humans, we will clarify key aspects of macrophage biology and contribute to the development of new therapeutic strategies.