Mechanosensing through surface receptor-cytoskeleton coupling in innate immune cells

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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.