Stromal-immune cell crosstalk promotes autoimmune valvular carditis - ABSTRACT: STROMAL-IMMUNE CELL CROSSTALK PROMOTES AUTOIMMUNE VALVULAR CARDITIS Understanding how immune cells and stromal cells interact and communicate with one another is critical in both normal physiology and pathophysiologic states. Such interactions dictate whether, in the face of a perturbation, the tissues will eventually return to normal physiologic function or whether the tissue will experience chronic changes such as fibrosis that may impact tissue and organ function. This proposal focuses on immune-stromal cell interactions in the cardiac valves. In human diseases including rheumatic heart disease (RHD), systemic lupus erythematosus, and related immune-driven conditions, the cardiac valves become inflamed. Over time, chronic inflammation leads to fibrosis, resulting in dysfunction of the valves and culminating eventually in heart failure. Therapies are currently limited, involving primarily surgical valve repair or replacement. Our laboratory has pioneered a mouse model of autoantibody-driven valvular carditis resembling these human conditions. We have shown key roles for particular immune cells (macrophages and B cells) as well as stromal cells (fibroblasts and endothelial cells). This proposal focuses on defining the pathways by which these immune and stromal cells communicate to perpetuate disease. In the first Aim, we will investigate whether fibroblasts – termed valve interstitial cells (VICs) – promote macrophage-mediated inflammation by producing the growth factor CSF-1. We will also determine if PDGF, produced primarily by immune cells, promotes VIC proliferation and activation to drive valve fibrosis. The second Aim builds on our recent description of new lymphatic endothelial cells and vessels emerging in the inflamed cardiac valves in this mouse model. The function of these lymphatic vessels remains incompletely defined. Building on our preliminary data, we will explore the hypothesis that these lymphatic endothelial cells produce the chemokine CCL21 that interacts with CCR7-expressing B cells to perpetuate local autoantibody-driven pathology in the cardiac valves. The proposed experiments involve conditional gene knockout approaches designed to provide cell-type specific mechanistic insight regarding these stromal-immune cell crosstalk pathways. Our studies will be the among the first to investigate these cellular communication pathways in the context of immune- mediated valvular carditis and to explore the function of the valve lymphatics we recently characterized. Furthermore, we have focused on pathways for which novel therapies are currently being developed, with the hope that identification of key molecular pathways could be translated rapidly to improve care for patients with RHD and related conditions.
