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Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis
Maria Sakkou, … , Niki Karagianni, George Kollias
Maria Sakkou, … , Niki Karagianni, George Kollias
Published April 5, 2018
Citation Information: JCI Insight. 2018;3(7):e98864. https://doi.org/10.1172/jci.insight.98864.
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Research Article

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

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Abstract

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

Authors

Maria Sakkou, Panagiotis Chouvardas, Lydia Ntari, Alejandro Prados, Kristin Moreth, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Maria C. Denis, Niki Karagianni, George Kollias

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Figure 1

Collagen 6a1-cre+ (Col6a1-cre+) cells are present in the ankle synovium and the aortic valve leaflets in the heart, where they colocalize with cardiac valvular interstitial cells (VICs).

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Collagen 6a1-cre+ (Col6a1-cre+) cells are present in the ankle synovium ...
Representative images of ankle joint and aortic valve leaflets from Col6a1-cre;R26mTm/mG mice (A) indicating cre-mediated GFP expression. Representative heart transverse sections stained with H&E and Lillie’s trichrome staining from WT and TnfΔARE/+ mice (B and C). Heart rate (D), cardiac output (E), ejection fraction (F), aortic peak velocity (G), and QTc interval quantifications (H), measured by ECG and Doppler echocardiography in 4 months. WT and TnfΔARE/+ mice as indicated (n = 29 mice per genotype), Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001. (I) Representative images of ankle joint and aortic heart valve leaflets from TnfΔARE/+;Col6a1-cre;R26mTm/mG mice showing increased number of GFP+ cells in both the inflamed ankle joint and the aortic valve (D). Scale bars: 200μm. s.m., synovial membrane; a.c., articular cartilage, p, pannus; v.l., valve leaflets; a.v.r., aortic valve root; CO, cardiac output; EF, ejection fraction; AoV, aortic peak velocity; QTc, time from the start of the Q wave to the end of the T wave on the ECG.

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