Autoimmune Valvular Carditis Requires Endothelial Cell TNFR1 Expression.
Arterioscler Thromb Vasc Biol
; 43(6): 943-957, 2023 06.
Article
en En
| MEDLINE
| ID: mdl-37021574
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 (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 TNFTNFR1 interaction could be beneficial in this clinical context.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores Tipo I de Factores de Necrosis Tumoral
/
Enfermedades de las Válvulas Cardíacas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2023
Tipo del documento:
Article