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.
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
Submitter: Pietro Enea Lazzerini | email@example.com
Authors: Pietro Enea LAZZERINI, Franco LAGHI-PASINI, Maurizio ACAMPA, Pier Leopoldo CAPECCHI.
University of Siena, Italy
Published May 31, 2018
It was with great interest that we read the article by Sakkou et al., recently published in JCI Insight. In our opinion, the finding reported by the authors that tumor necrosis factor-α (TNFα)- overexpressing mice developing chronic polyarthritis (TnfΔARE) also showed prolongation of heart rate-corrected QT interval (QTc) at the electrocardiogram (ECG) should be emphasized. In fact, in connection with other data recently published by the same research group, this finding might help clarify the mechanisms underlying premature mortality in patients with chronic inflammatory arthritis (CIA), i.e. rheumatoid arthritis (RA) and spondyloarthtis.
QTc prolongation, a well-established predictor of fatal ventricular arrhythmias and sudden cardiac death (SCD) in the general population, is a common clinical feature in CIA, also correlating with disease activity and inflammatory markers. Accordingly, increasing evidence indicates that in these patients systemic inflammation can increase myocardial electric instability by both accelerating structural cardiovascular disease development and directly affecting cardiac electrophysiology. In RA patients, who have a two-fold higher risk of cardiac arrest and SCD when compared to the general population[5,6], QTc prolongation is associated with circulating cytokine levels[7,8] and independently predicts all-cause mortality. However, to date no studies directly demonstrated that in CIA there is an increased incidence of fatal arrhythmic events, nor that the presence of QTc prolongation is a specific predictor of life-threatening ventricular arrhythmias and SCD in these patients.
The paper by Sakkou et al.  provided for the first time direct evidence in an animal model that induction of a TNF-driven chronic polyarthritis is concomitantly associated with QTc prolongation development. On one hand, this finding confirms in-vivo the relevance of in-vitro experiments demonstrating that TNFα can prolong ventricular action potential duration (reflected on the surface ECG by the QTc length) by reducing the expression and/or function of several K+-currents, including IKr, Ito, and IKs[4,10]. On the other hand, the concomitant evidence recently reported by the same authors in another TNFα-overexpressing mouse model of polyarthritis (Tg197) that these animals shows premature mortality along with high incidence of fatal arrhythmias, strongly points to TNFα-induced QTc prolongation as a potential underlying mechanism linking such two events.
These data may have important clinical implications. In our opinion, they warrant large population studies to define the prevalence of life-threatening arrhythmias and SCD in CIA, as well as the predictive role of QTc prolongation, and circulating cytokines, particularly TNFα. Moreover, the specific impact of anti-cytokine biological drugs on arrhythmic events and SCD should be also evaluated. Indeed, it is demonstrated that both anti-TNFα-therapy and IL-6 blockade rapidly shortened QTc in CIA, in the last case in strict association with circulating TNFα levels decrease. Intriguingly, the recent evidence from the CARLA study demonstrating that TNFα system activation is independently associated with QTc duration also in the general population, might unexpectedly expand the significance of the results possibly deriving from such studies.
Sakkou M, Chouvardas P, Ntari L, Prados A, Moreth K, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Denis MC, Karagianni N, Kollias G. Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis. JCI Insight 2018;3(7).
Ntari L, Sakkou M, Chouvardas P, Mourouzis I, Prados A, Denis MC, Karagianni N, Pantos C, Kollias G. Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis. Ann Rheum Dis 2018;77:926-934.
 Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, Philippides GJ, Roden DM, Zareba W; American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular Nursing; American College of Cardiology Foundation. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation 2010;121:1047-1060.
 Lazzerini PE, Capecchi PL, Laghi-Pasini F. Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 2017;38:1717-1727
 Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Ballman KV, Roger VL, Jacobsen SJ, et al. Increased unrecognized coronary heart disease and sudden death in rheumatoid arthritis. A population-based cohort study. Arthritis Rheum 2005;52:402-411.
 Pujades-Rodriguez M, Duyx B, Thomas SL, Stogiannis D, Rahman A, Smeeth L, Hemingway H. Rheumatoid Arthritis and Incidence of Twelve Initial Presentations of Cardiovascular Disease: A Population Record-Linkage Cohort Study in England. PLoS One 2016 Mar 15;11(3):e0151245.
 Adlan AM, Panoulas VF, Smith JP, Fisher JP, Kitas GD. Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis. J Rheumatol 2015;42:421-428.
 Lazzerini PE, Acampa M, Capecchi PL, Fineschi I, Selvi E, Moscadelli V, Zimbone S, Gentile D, Galeazzi M, Laghi-Pasini F.Antiarrhythmic potential of anti-cytokine therapy in rheumatoid arthritis: Tocilizumab reduces QTc interval by controlling systemic inflammation. Arthritis Care Res 2015;67:332-339.
 Panoulas VF, Toms TE, Douglas KM, Sandoo A, Metsios GS, Stavropoulos-Kalinoglou A, Kitas GD. Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: an association driven by high inflammatory burden. Rheumatology 2014;53:131-137.
 Wang J, Wang H, Zhang Y, Gao H, Nattel S, Wang Z. Impairment of HERG K(+) channel function by tumor necrosis factor-alpha: role of reactive oxygen species as a mediator. J Biol Chem 2004;279:13289-13292.
 Senel S, Cobankara V, Taskoylu O, Guclu A, Evrengul H, Kaya MG. Effect of infliximab treatment on QT intervals in patients with ankylosing spondylitis. J Investig Med 2011;59:1273-1275.
 Medenwald D, Kors JA, Loppnow H, Thiery J, Kluttig A, Nuding S, Tiller D, Greiser KH, Werdan K, Haerting J. Inflammation and prolonged QT time: results from the Cardiovascular Disease, Living and Ageing in Halle (CARLA) study. PLoS One 2014;9:e95994