Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension
Soni Savai Pullamsetti, Werner Seeger, and Rajkumar Savai
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Justus Liebig University, Giessen, Germany. Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the DZL, Bad Nauheim, Germany.
Address correspondence to: Soni Savai Pullamsetti, Molecular Mechanisms of Pulmonary Vascular Diseases, Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Parkstrasse 1, D-61231 Bad Nauheim, Germany. Phone: 49.6032.705.380; Email: soni.pullamsetti@mpi-bn.mpg.de.
Find articles by Pullamsetti, S. in: JCI | PubMed | Google Scholar
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Justus Liebig University, Giessen, Germany. Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the DZL, Bad Nauheim, Germany.
Address correspondence to: Soni Savai Pullamsetti, Molecular Mechanisms of Pulmonary Vascular Diseases, Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Parkstrasse 1, D-61231 Bad Nauheim, Germany. Phone: 49.6032.705.380; Email: soni.pullamsetti@mpi-bn.mpg.de.
Find articles by Seeger, W. in: JCI | PubMed | Google Scholar
Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Justus Liebig University, Giessen, Germany. Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the DZL, Bad Nauheim, Germany.
Address correspondence to: Soni Savai Pullamsetti, Molecular Mechanisms of Pulmonary Vascular Diseases, Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Parkstrasse 1, D-61231 Bad Nauheim, Germany. Phone: 49.6032.705.380; Email: soni.pullamsetti@mpi-bn.mpg.de.
Find articles by Savai, R. in: JCI | PubMed | Google Scholar
First published April 9, 2018 - More info
J Clin Invest. 2018;128(5):1720–1723. https://doi.org/10.1172/JCI120415.
Copyright © 2018, American Society for Clinical Investigation
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Abstract
Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo. Using Sm22a-Cre Il6rfl/fl, which lack Il6r in SM22A-expressing cells, we found that these animals are protected against chronic hypoxia–induced PH with reduced PA-SMC accumulation, revealing the potent pro-survival potential of membrane-bound IL6R. Moreover, we determine that treatment with IL6R-specific antagonist reverses experimental PH in two rat models. This therapeutic strategy holds promise for future clinical studies in PAH.
Authors
Yuichi Tamura, Carole Phan, Ly Tu, Morane Le Hiress, Raphaël Thuillet, Etienne-Marie Jutant, Elie Fadel, Laurent Savale, Alice Huertas, Marc Humbert, Christophe Guignabert
Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL-6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH.
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Copyright © 2018 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)