The role of synovial tissue macrophage VSIG4 in regulating joint immune-homeostasis

Challenge Addressed by the Project: Understanding the cellular and molecular mechanisms that maintain joints in a self-regulated, healthy immune state. Rheumatoid arthritis (RA) occurs when the immune system attacks the joints (autoimmune attack), leading to reduced quality-of-life and an increased risk of heart attacks and strokes. Although treatments targeting pathogenic cells and molecules have improved RA management, around 40% of patients do not achieve remission, and approximately 50% of those who do experience flare-ups if treatment is stopped. Only 10-20% of patients maintain treatment-free remission for up to two years, with a persistent risk of relapse. This poses a significant challenge for patients, society, and healthcare systems. The majority patients in remission have ongoing immune system issues, such as harmful T-cells and immune-complexes in circulation. While these normally do not cause symptoms, if they enter the joints and are not controlled, they can induce joint pathology and disease flare-ups. Our goal is to identify the tissue mechanisms that restore the joint’s ability to control the autoimmune attack. Aims: We recently discovered that while many inflammation-resolving pathways are reactivated in patients in remission—helping to maintain remission after drug withdrawal—there is one notable exception. Most patients do not restore a specific tissue macrophage pathway, VSIG4, which is present at high levels in healthy joints. Preliminary data suggest that VSIG4 may play a crucial role in keeping autoimmune triggers, such as harmful T-cells and immune-complexes, at bay within tissues. We propose to test this experimentally using targeted animal models and synovial tissue assays designed to mimic autoimmune attacks. Objectives: (a) Determine how VSIG4 activity in a specific population of synovial tissue macrophages (referred to as lining-layer TREM2pos STMs) controls joint autoimmune attacks. To achieve this, we will investigate what happens in the joints of mice that specifically lack VSIG4 in TREM2pos STMs after introducing potentially harmful T-cells. Additionally, we will examine how human TREM2pos STMs isolated from healthy joints handle autoreactive-T-cells when VSIG4 is switched off, and explore methods to reinstate the expression of VSIG4 in the joints of patients in remission. (b) Understand how VSIG4-positive macrophages regulate adjacent cells in tissue and uncover additional mechanisms essential for maintaining joint health. We will construct a detailed spatial map of healthy joint tissue to gain insights into the function of each cell within its specific tissue niche. By comparing this data with tissue samples from patients with RA, including those in remission, we will uncover how VSIG4-expressing macrophages influence neighbouring cells in a healthy state to protect against pathology. This analysis will help us understand which immune-protective processes driven by VSIG4 and other pathways are missing in remission, hindering recovery. Benefits: Our research will enhance our understanding of how healthy joints control autoimmune attacks. This insight will lead to the development of new strategies to prevent disease flare-ups, such as restoring VSIG4 expression in joints and/or enhancing its activation through agonistic antibodies. Additionally, understanding the mechanisms essential for maintaining joint immune homeostasis will establish cellular and molecular standards for both existing and future drugs in experimental and clinical development. This insight could transform the fragile state of remission defined by current criteria into a more stable, self-regulated condition that more closely resembles a healthy joint.