Abstract 575: Impact Of Resident Macrophages On Fibrosis And Lymphatic Growth During Autoimmune Valvular Carditis

Abstract

Rheumatic diseases are associated with increased cardiovascular disease and the mitral valve (MV) is one of the tissues most commonly affected. Valve disease prevalence continues to rise yet the mechanisms driving autoimmune valvular carditis are incompletely understood, limiting treatment options. Our team has previously demonstrated a role for macrophages in promoting MV disease in the K/B.g7 mouse model of autoantibody-induced arthritis and valvular carditis. To further characterize the MV macrophage populations, we conducted single cell RNA sequencing of healthy (B.g7) and inflamed (K/B.g7) MVs. Analysis revealed multiple macrophage populations including Ccr2 + Bhlhe40 + recruited, pro-inflammatory macrophages and Mrc1 + Cd63 + resident macrophages, which we further validated by flow cytometry. These findings raised new questions regarding which subset(s) of macrophages influence disease progression and how. Within the resident population, we identified a subset of Lyve1 + Folr2 + macrophages. Immunostaining demonstrated that this macrophage subset localizes along the valve endothelium and near lymphatic vessels that we have recently demonstrated emerge in inflamed valves and promote valve disease. Importantly, we also found LYVE1+ macrophages co-localized with lymphatics in human MVs. Prior studies demonstrate that LYVE1+ macrophages are important regulators of vessel growth and extracellular matrix regulation. Thus, we hypothesized that LYVE1+ resident macrophages promote MV disease by augmenting lymphatic growth and contributing to changes in extracellular matrix. To understand the potential functions of these cells, we depleted Lyve1 -expressing macrophages in vivo by crossing Lyve1 -Cre mice with the Csf1r -floxed mice. We found that valves from LYVE1+ macrophage-depleted non-inflamed mice have increased collagen deposition, suggesting these macrophages are important for restraining extracellular matrix deposition. Studies are underway to determine if these resident macrophages promote fibrosis and lymphatic growth in the pro-inflammatory environment of the K/B.g7 model. Outcomes from these studies will have important implications for other cardiovascular and fibrotic diseases.