Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis

• DOI: 10.1172/jci.insight.98864
• Publication Date: 2018-04-04T15:00:55Z
• Authors: Maria Sakkou; Panagiotis Chouva...; Lydia Ntari; Alejandro Prados; Kristin Moreth; Helmut Fuchs; Valerie Gailus-Du...; Martin Hrabe de A...; Maria C. Denis; Niki Karagianni; George Kollias
• Keywords: Inflammatory arthritis

Mesenchymal TNF signaling is etiopathogenic for inflammatory diseases such as rheumatoid arthritis and spondyloarthritis (SpA). The role of Tnfr1 in has been documented; however, Tnfr2 functions are unknown. Here, we investigate the mesenchymal-specific TnfΔARE mouse model SpA heart valve stenosis comorbidity by cell-specific, Col6a1-cre-driven gene targeting. We find that TNF/Tnfr2 resident synovial fibroblasts (SFs) valvular interstitial cells (VICs) detrimental both pathologies, pointing to common cellular mechanisms. In contrast, systemic provides protective signaling, since its complete deletion leads severe deterioration pathologies. SFs VICs lacking fail acquire pathogenic activated phenotypes display increased expression antiinflammatory cytokines associated with decreased Akt signaling. Comparative RNA sequencing experiments showed majority deregulated pathways mesenchymal-origin VICs, including proliferation, inflammation, migration, disease-specific genes, regulated Tnfr2; thus, absence, they maintained a quiescent nonpathogenic state. Our data indicate pleiotropy functions, mesenchymal driving cell activation arthritis/valve pathogenesis only presence Tnfr2, whereas nonmesenchymal overcomes this function, providing signals and, containing