Immunoproteomic identi cation of in vivo response toward residual antigenic proteins in xenogeneic heart valve biomaterials
Rheumatic heart disease (RHD) is a major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to RHD, but greater insight into contributing mechanisms is needed. Cdh5-driven EC lineage tracing in the K/B.g7 mouse model of autoimmune valvular carditis revealed new capillary lymphatic vessels that develop from valve surface endothelial cells during the progression of disease. Human rheumatic valves contained similar lymphatics. Unsupervised clustering of mitral valve single-cell RNA sequencing data revealed lymphatic valve ECs (VECs) that express a transcriptional profile distinct from other VEC populations and upregulate genes controlling extracellular matrix composition and fibrosis during disease progression. Finally, inhibiting VEGFR3 prevented expansion of this mitral valve lymphatic network and decreased valve thickening and collagen density. These studies reveal a novel form of postnatal pathogenic lymphangiogenesis that promotes autoimmune valvular carditis.
BACKGROUND: Inflammation is a key driver of cardiovascular pathology, and many systemic autoimmune/rheumatic diseases are accompanied by increased cardiac risk. In the K/B.g7 mouse model of coexisting systemic autoantibody-mediated arthritis and valvular carditis, valve inflammation depends on macrophage production of TNF and IL-6. Here, we sought to determine if other canonical inflammatory pathways participate and to determine whether TNF signaling through TNFR1 on endothelial cells is required for valvular carditis. METHODS: We first asked if type 1, 2, or 3 inflammatory cytokine systems (typified by IFNγ, IL-4, and IL-17, respectively) were critical for valvular carditis in K/B.g7 mice, using a combination of in vivo monoclonal antibody blockade and targeted genetic ablation studies. To define the key cellular targets of TNF, we conditionally deleted its main proinflammatory receptor, TNFR1, in endothelial cells. We analyzed how the absence of endothelial cell TNFR1 affected valve inflammation, lymphangiogenesis, and the expression of proinflammatory genes and molecules. RESULTS: We found that typical type 1, 2, and 3 inflammatory cytokine systems were not required for valvular carditis, apart from a known initial requirement of IL-4 for autoantibody production. Despite expression of TNFR1 on a wide variety of cell types in the cardiac valve, deleting TNFR1 specifically on endothelial cells protected K/B.g7 mice from valvular carditis. This protection was accompanied by reduced expression of VCAM-1 (vascular cell adhesion molecule), fewer valve-infiltrating macrophages, reduced pathogenic lymphangiogenesis, and diminished proinflammatory gene expression. CONCLUSIONS: TNF and IL-6 are the main cytokines driving valvular carditis in K/B.g7 mice. The interaction of TNF with TNFR1 specifically on endothelial cells promotes cardiovascular pathology in the setting of systemic autoimmune/rheumatic disease, suggesting that therapeutic targeting of the TNF:TNFR1 interaction could be beneficial in this clinical context.
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