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

巨噬细胞是一种专业的吞噬细胞，存在于大多数后生动物生物体中。研究表明，许多巨噬细胞群都是来源于胚胎祖细胞的长寿命细胞。巨噬细胞在每个组织中发挥特殊的功能，并高度适应宿主环境。最近的研究指出，即使在一个组织内，脊椎动物组织的巨噬细胞亚群也具有高度的多样性。然而，人们对这些子集的多样化机制或确切功能了解较少。此外，脊椎动物组织巨噬细胞亚群的靶向和操作既耗时又昂贵，在技术上仍然具有挑战性，并受到有限的基因工具库的阻碍。浆细胞是果蝇的巨噬细胞样细胞，与脊椎动物的巨噬细胞有着深刻的相似之处。这些包括类似的发育和相似的功能，如吞噬细胞碎片和入侵病原体或分泌免疫调节因子。在成虫体内，95%的血细胞实际上是来源于胚胎、幼虫和淋巴腺造血的浆细胞。除了作为成年果蝇抵抗感染的第一道防线的基本功能外，我们和其他人进一步证明了浆细胞在稳定状态下调节组织动态平衡和新陈代谢方面发挥着重要作用，并在高脂饮食等慢性应激反应中发挥不利作用。因此，果蝇浆细胞为研究组织巨噬细胞的功能提供了很好的工具。我们希望利用模式生物黑腹果蝇及其独特的遗传工具箱来明确和鉴定功能性巨噬细胞/浆细胞异质性及其潜在机制。我们的目标是了解成年果蝇巨噬细胞在造血来源、基因表达和在健康和疾病中的功能方面的异质性。因此，我们将使用大量不同的遗传模型，并结合新的先进技术，如体内成像或scRNA-seq。通过与小鼠巨噬细胞数据的比较，我们的研究将对组织巨噬细胞的特性和不同亚群的功能提供进一步的见解。这些数据将进一步有助于更好地理解组织环境和不同的疾病环境如何决定从苍蝇到人类的各种物种的巨噬细胞功能。了解果蝇中巨噬细胞的异质性将使我们能够确定无脊椎动物和脊椎动物之间共同和不同的巨噬细胞指定机制。

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.