Macrophage diversity: nature vs. nurture

巨噬细胞是一种长寿的免疫细胞，它提供了对抗非自我的第一道防线。它们还作为局部和系统的信号中枢，协调组织的内稳态和功能。此外，巨噬细胞是癌症和神经变性等多种疾病的主要参与者，具有依赖于环境的有益或有害影响。因此，这些细胞代表了强大的治疗靶点，但它们的多样性，这可能导致它们在病理条件下的不同作用，仍然是一个主要的，但知之甚少的特征。因此，确定可塑性和适应性与谱系特异性对巨噬细胞功能的相对影响是基础科学和医学中的一个重大挑战。因此，巨噬细胞多样化过程中分子检查点的识别，取决于它们的个体发生和组织环境，也取决于所遇到的挑战，可能允许巨噬细胞在疾病期间调节和重置。在这里，我们计划通过结合谱系追踪、转录组学（批量/单细胞分辨率）和功能分析，以及遗传和药理学操作，剖析无脊椎动物和脊椎动物巨噬细胞多样性的基础和影响。因此，我们确定了在这个项目中我们将重点关注的三个具体目标。首先，我们将定义巨噬细胞异质性是否反映了不同的细胞状态或身份。接下来，我们将评估不同造血波产生的巨噬细胞亚群之间的差异，最后，我们将评估短期和长期挑战对果蝇巨噬细胞可塑性的影响，并与小鼠结果进行比较。为此，我们将利用法国团队（A. Giangrande）在苍蝇巨噬细胞多样性、表观遗传学和发育方面的互补专业知识，以及德国团队（K. Kierdorf）在苍蝇和小鼠巨噬细胞生理学和组织规范方面的互补专业知识。我们还将与J. Shim（首尔）和T. Mukherjee（班加罗尔）的团队进行互动，他们对代谢和转录巨噬细胞特征有共同的兴趣。鉴于从果蝇到人类的主要生物学过程的进化守恒，我们将阐明巨噬细胞生物学的关键方面，并有助于开发新的治疗策略。

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.