Mechanosensing through surface receptor-cytoskeleton coupling in innate immune cells

免疫系统的作用是保护我们的身体，使其保持良好的运作秩序。这种保护的关键是区分正常健康组织与异常或侵袭性实体的能力。先天免疫系统的细胞，如巨噬细胞和树突细胞，生活在身体的每一个组织中，并作为免疫系统的哨兵。它们具有识别受损细胞和入侵实体（如微生物）的精致能力，并通过称为吞噬作用的过程将其清除。对于正常的免疫功能来说，巨噬细胞（来自希腊语的大食者）不会吃掉周围的一切，这一点至关重要。那么巨噬细胞是如何识别吃什么的呢？巨噬细胞必须为任何类型的异常实体做好准备;因此，它们识别正常组织中没有的一般特征。例如，它们可以识别哺乳动物中不存在的分子，这意味着它们必须来自不同的生物体。最近，我们发现巨噬细胞也可以识别它们试图吃掉的实体的物理特征。大多数微生物的物理特征与哺乳动物细胞非常不同;它们具有各种大小和形状，并且非常坚硬。我们已经证明，巨噬细胞通过一种称为补体受体3的受体识别其靶标的硬度。然而，使巨噬细胞能够识别硬度的内部机制，也称为机械感应，是未知的。这项研究计划的首要目标是了解免疫细胞如何识别周围物体的硬度。在这项提案中，我们专注于补体受体3（CR 3）使机械传感的机制。为了确定这些机制，我们将使用尖端的显微镜技术来可视化和量化巨噬细胞如何产生和施加在其目标上的力，以响应其硬度。具体来说，我们将：1）揭示CR 3附着特性对机械传感的作用。2)确定吞噬细胞靶标的机械特性如何调节CR 3与细胞骨架的偶联。3)确定CR 3介导的机械传感如何调节细胞骨架动力学。这项研究计划将揭示基本机制，帮助我们了解免疫系统如何工作。考虑到机械传感在许多生物过程（例如，包括组织发育，细胞分化，增殖和迁移）中起着重要作用，更好地理解机械传感如何工作将在生物科学中产生广泛的影响。除了产生基础知识，该研究计划将提供优秀的机会，培养学生先进和独特的技能（例如基因编辑，定量显微镜，数字图像处理），使他们能够在生命科学技术和创新方面获得有竞争力的职业。

The role of the immune system is to protect our body and keep it in good functioning order. A key to this protection is the ability to distinguish normal heathy tissues from abnormal or aggressive entities. Cells of the innate immune system, such as macrophages and dendritic cells, live in every tissue of the body and act as sentinels of the immune system. They have an exquisite ability to recognize damaged cells and invasive entities, such as microbes, and to remove them through a process termed phagocytosis. It is crucial for proper immune function that macrophages (large eaters, from Greek) do not eat everything around them. So how do macrophages recognize what to eat? Macrophages must be ready for any kind of abnormal entities; thus, they recognize general features that are not found in normal tissues. For example, they can recognize molecules that do not exist in mammals, meaning that they must come from a different organism. Recently, we discovered that macrophages can also recognize the physical characteristics of the entities they try to eat. The physical characteristics of most microbes are very different from mammalian cells; they have various sizes and shapes, and they are very stiff. We have demonstrated that macrophages recognize the stiffness of their target through a receptor called Complement Receptor 3. However, the internal mechanism that enables macrophages to recognize stiffness, also called mechanosensing, is unknown. The overarching goal of this research program is to understand how immune cells recognize the stiffness of surrounding objects. In this proposal, we focus on the mechanisms that enable mechanosensing by the Complement Receptor 3 (CR3). To identify these mechanisms, we will use cutting edge microscopy techniques to visualize and quantify how macrophages generate and apply forces on their target, in response to its stiffness. Specifically, we will: 1) Reveal the role of CR3 attachment properties for mechanosensing. 2) Establish how the mechanical properties of the phagocytic target regulate the coupling of CR3 to the cytoskeleton. 3) Determine how CR3-mediated mechanosensing regulates cytoskeleton dynamics. This research program will reveal fundamental mechanisms that will help us to understand how the immune system works. Considering that mechanosensing plays an important role in many biological processes (e.g. including tissue development, cell differentiation, proliferation and migration), a better understanding of how mechanosensing works will have a broad impact in biological sciences. In addition to generating fundamental knowledge, this research program will provide outstanding opportunities to train students in advanced and unique skills (e.g. gene editing, quantitative microscopy, digital image processing) that will position them for competitive careers in life science technologies and innovation.