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

成年果蝇组织巨噬细胞的异质性-健康和疾病中巨噬细胞亚群的表征和鉴定

• 批准号: 432207796
• 负责人: Professorin Dr. Katrin Kierdorf
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432207796?language=en
• 关键词: Heterogeneity; tissue; macrophages; adult; Drosophila

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.

巨噬细胞是在大多数后生动物中发现的专职吞噬细胞。研究表明，许多巨噬细胞群体是来自胚胎祖细胞的长寿细胞。巨噬细胞在每个组织中发挥专门的功能，并高度适应其宿主环境。最近的研究指出，脊椎动物组织巨噬细胞亚群的高度多样性，即使在一个组织。然而，对这些子集的多样化机制或确切功能的了解较少。此外，脊椎动物组织巨噬细胞亚群的靶向和操纵是耗时的、昂贵的，并且仍然在技术上具有挑战性，并且受到有限的遗传工具库的阻碍。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。这些包括类似的发展和类似的功能，如吞噬细胞碎片和入侵病原体或分泌免疫调节因子。在成蝇中，95%的血细胞实际上是来自胚胎、幼虫和淋巴腺造血的浆细胞。除了它们作为成年果蝇抗感染的第一道防线的基本功能之外，我们和其他人进一步证明了浆细胞在稳态下调节组织稳态和代谢方面具有重要功能，并且在慢性应激反应中发挥有害作用，例如高脂饮食。因此，果蝇浆细胞为研究组织巨噬细胞的功能提供了一个很好的工具。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指定和识别功能性巨噬细胞/浆细胞异质性及其潜在机制。我们的目的是了解巨噬细胞异质性在成年果蝇的造血起源，基因表达和功能的健康和疾病。因此，我们将采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。与小鼠巨噬细胞的数据相比，我们的研究将进一步了解组织巨噬细胞的特性和不同亚群的功能。这些数据将进一步导致更好地了解组织环境和不同疾病环境如何决定从苍蝇到人类的跨物种巨噬细胞功能。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的巨噬细胞特异性的共同和不同的机制。