Inflammatory arthritis patients who achieve drug-free remission show a specific molecular handshake between two cell types in their joints—and that handshake is missing during flare-ups. This matters because medicine has long assumed that recovery from inflammation is a passive process of simply turning off the immune system. The researchers’ earlier work on human tissue suggests it is actually an active, coordinated effort between immune cells called TREM2-positive macrophages and structural cells called synovial fibroblasts. The macrophages carry a receptor (MerTK) that binds to a signal molecule (GAS6) produced by the fibroblasts. The project will test whether this binding is what drives the joint back to a healthy, balanced state. If the hypothesis holds, it would reveal a fundamental mechanism of tissue repair that likely operates in other organs as well. The project will create two concrete tools for the research community: a new strain of transgenic mice to study GAS6 from fibroblasts, and a validated lab-grown model of human joint tissue called a synovial organoid. These tools could eventually help researchers design therapies that actively push inflamed tissues toward recovery rather than just suppressing inflammation.
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Project Challenge: This project aims to understand how tissue returns to a healthy state after inflammation. Recent studies in humans and mice show that disease resolution isn’t just about eliminating harmful processes; it involves an active effort to restore immune balance in the affected area. Gaining more knowledge about these healing processes is important for finding ways to help organs recover from diseases. In our previous research on tissue samples from patients with inflammatory arthritis who achieved recovery and remained symptom-free without medication, we discovered a significant interplay between two cell types that may facilitate the restoration of a healthy state—an interaction that was notably absent in joints experiencing inflammatory flare-ups. Based on this preliminary data, we hypothesize that the binding of a receptor (MerTK) expressed by cells called TREM2pos synovial tissue macrophages to its ligand (GAS6), produced locally by joint structural cells known as synovial fibroblasts, may drive the restoration of healthy immune balance (homeostasis) in the joint. We propose to experimentally test this hypothesis using specially designed animal models and three-dimensional cell-organ structures known as synovial-organoids, which mimic human joint tissues. We will specifically: Investigate how MerTK from TREM2pos synovial tissue macrophages helps resolve inflammation and rebuild the tissue structure. Explore the contribution of GAS6 from neighbouring synovial fibroblasts to these restorative processes. To achieve this, we will investigate whether the return to a healthy immune balance in joints is impaired when MerTK (receptor) is specifically absent in TREM2pos synovial tissue macrophages, or when GAS6 (ligand) is absent in synovial fibroblasts. Additionally, we will examine the effects of switching these molecules on and off on the resolution of inflammation and the restoration of tissue structure in humans, using synovial organoids. This analysis will help determine the essential roles of MerTK in TREM2pos macrophages and GAS6 from fibroblasts in restoring and maintaining joint tissue in healthy immune balance. To ensure the success of this project, we have assembled a collaborative team from Glasgow and Oxford, bringing together complementary expertise in macrophage and fibroblast biology, tissue resources, and experience in generating transgenic models. Benefits. Our research will provide novel insights into the conserved mechanisms in both mice and humans that restore and maintain a healthy immune balance in joints. Understanding these fundamental processes of tissue regulation following an immune response may have applications to other tissues. This knowledge could inform the development of innovative strategies to restore tissue functions after diseases. Furthermore, this project will create valuable resources for the scientific community, including a new strain of transgenic mice to study the role of GAS6 from fibroblasts in tissue homeostasis, as well as a validated synovial organoid model.
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