Autoimmune Valvular Carditis Requires Endothelial Cell TNFR1 Expression

Abstract

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.

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis

“…We have shown that TGFβ signaling via the TGFβR2 on ECs does not affect valve disease progression, but it remains possible that TGFβ action on fibroblasts regulates disease progression. 7 Future lymphatic inhibitor and genetic studies (including macrophage-and fibroblast-specific knockouts) with discrete timing considerations will be needed to test these hypotheses and to understand more fully the functional roles of lymphatics, fibroblasts, and macrophages in the inflamed mitral valve.…”