Key result
Endothelial TNFR1 deletion protects against autoimmune valvular carditis, whereas blocking major inflammatory cytokines fails.
Demonstrates that endothelial cell TNFR1 expression drives autoimmune valvular carditis in mice, suggesting targeting the TNF:TNFR1 pathway protects against rheumatic heart damage.
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 (tumor necrosis factor) and IL-6 (interleukin-6). Here, we sought to determine if other canonical inflammatory pathways participate and to determine whether TNF signaling through TNFR1 (tumor necrosis factor receptor 1) 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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Faragher et al. (2023) studied Autoimmune valvular carditis and systemic autoantibody-mediated arthritis. Conditional deletion of TNFR1 in endothelial cells and in vivo monoclonal antibody blockade / targeted genetic ablation of IFNγ, IL-4, and IL-17 vs. Control K/B.g7 mice with intact endothelial TNFR1 expression was evaluated on Protection from valvular carditis (valve inflammation, VCAM-1 expression, macrophage infiltration, pathogenic lymphangiogenesis, and proinflammatory gene expression). Endothelial cell-specific deletion of TNFR1 protected K/B.g7 mice from autoimmune valvular carditis, whereas blocking type 1, 2, or 3 inflammatory cytokines did not.
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