Heterogeneity of tissue macrophages in adult Drosophila melanogaster-Characterization and identification of macrophage subsets in health and disease

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Macrophages are professional phagocytes found throughout most metazoan organisms. It was shown that many macrophage populations are long-lived cells which are derived from embryonic progenitors. Macrophages serve specialized functions in each tissue and are highly adapted to their host environment. Recent studies point to a high diversity of vertebrate tissue macrophage subsets even within one tissue. However, less is understood about the mechanisms of diversification or the precise functionality of these subsets. Furthermore, the targeting and manipulation of vertebrate tissue macrophage subsets is time consuming, pricy and still technically challenging and hampered by a limited repertoire of genetic tools. Plasmatocytes, the macrophage-like cells of Drosophila melanogaster, display profound similarities to vertebrate macrophages. Those include analogous development and similar functions, such as phagocytosis of cell debris and invading pathogens or secretion of immune modulatory factors. In the adult fly, 95% of all hemocytes are actually plasmatocytes derived from embryonic, larval and lymph gland hematopoiesis. Besides their essential functions as a first line of defense against infections in the adult fly, we and others further demonstrated that plasmatocytes serve important functions in regulating tissue homeostasis and metabolism under steady state and play detrimental roles in chronic stress responses, such as high fat diet. Drosophila plasmatocytes therefore offer a great tool to study functions of tissue macrophages. We want to take advantage of the model organism Drosophila melanogaster and its unique genetic tool box to specify and identify functional macrophage/plasmatocyte heterogeneity and its underlying mechanisms. We aim to understand macrophage heterogeneity in adult Drosophila in terms of hematopoietic origin, gene expression and function in health and disease. Therefore we will employ a plethora of different genetic models combined with new advanced technologies, such as in vivo imaging or scRNA-seq. In comparison to data of mouse macrophages, our study will give further insights on the specification of tissue macrophages and the function of different subsets. The data will further lead to a better understanding on how tissue environment and different disease settings determines macrophage function across species from fly to human. Understanding the macrophage heterogeneity in Drosophila will allow us to determine common and distinct mechanisms of macrophage specification between invertebrates and vertebrates.