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Published on: September 15, 2017
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Autoimmune Valvular Carditis Requires Endothelial Cell TNFR1 Expression.
Jessica L Faragher1,2,3, Jennifer L Auger1,2,3, Victoria Osinski1,2,3
1Center for Immunology (J.L.F., J.L.A., V.O., L.A.M., B.J.E., B.A.B.).
Arteriosclerosis, Thrombosis, and Vascular Biology
|April 6, 2023
Summary
Tumor necrosis factor (TNF) and IL-6 drive valvular carditis in mice. Blocking TNF signaling via TNFR1 on endothelial cells protects against this cardiac pathology, suggesting a therapeutic target for autoimmune diseases.
Area of Science:
- Cardiovascular Pathology
- Immunology
- Rheumatology
Background:
- Inflammation significantly contributes to cardiovascular disease, with systemic autoimmune/rheumatic conditions increasing cardiac risk.
- In K/B.g7 mice with arthritis and valvular carditis, macrophage-derived TNF and IL-6 are crucial for valve inflammation.
- This study investigated other inflammatory pathways and the role of TNF receptor 1 (TNFR1) on endothelial cells in valvular carditis.
Purpose of the Study:
- To determine if type 1, 2, or 3 inflammatory cytokine systems are essential for valvular carditis.
- To investigate the role of TNF signaling through TNFR1 on endothelial cells in the development of valvular carditis.
- To analyze the impact of endothelial cell TNFR1 deletion on valve inflammation, lymphangiogenesis, and gene expression.
Main Methods:
- Utilized monoclonal antibody blockade and genetic ablation to assess the necessity of type 1, 2, and 3 inflammatory cytokine systems.
- Created a conditional knockout mouse model to specifically delete TNFR1 in endothelial cells.
- Evaluated valvular carditis, valve inflammation, lymphangiogenesis, and gene expression in the absence of endothelial TNFR1.
Main Results:
- Type 1, 2, and 3 inflammatory cytokine systems were not required for valvular carditis, except for an initial IL-4 role in autoantibody production.
- Conditional deletion of TNFR1 in endothelial cells significantly protected K/B.g7 mice from valvular carditis.
- Protection was associated with reduced VCAM-1 expression, fewer infiltrating macrophages, decreased lymphangiogenesis, and lower proinflammatory gene expression.
Conclusions:
- TNF and IL-6 are the primary drivers of valvular carditis in the K/B.g7 mouse model.
- TNF signaling via TNFR1 specifically on endothelial cells promotes cardiovascular pathology in autoimmune settings.
- Targeting the TNF:TNFR1 interaction presents a potential therapeutic strategy for related clinical conditions.
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