Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension
Yuichi Tamura, … , Marc Humbert, Christophe Guignabert
Yuichi Tamura, … , Marc Humbert, Christophe Guignabert
Published April 9, 2018
Citation Information: J Clin Invest. 2018;128(5):1956-1970. https://doi.org/10.1172/JCI96462.
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Research Article Vascular biology

Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension

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

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Figure 1

Upregulation of IL-6 cis- and trans-signaling pathways in PA-SMCs and lungs of patients with iPAH as compared with control patients.

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Upregulation of IL-6 cis- and trans-signaling pathways in PA-SMCs and lu...
(A) Double staining with IL6R, pSTAT3, or gp130 with SM22 and DAPI in lungs from control subjects and iPAH patients (n = 7). (B) Representative Western blots and quantification of IL6R/β-actin, pSTAT3/STAT3, and gp130/β-actin ratios in human pulmonary PA-SMCs derived from control subjects and iPAH patients (n = 6–8). (C) Representative Western blots and quantification of pSTAT3/STAT3 ratio in human pulmonary PA-SMCs derived from control subjects and iPAH patients exposed for 0, 15, or 30 minutes to rHuIL-6 protein (n = 5–6). Scale bars: 50 μm. Data are presented as mean ± SEM. Comparisons were made using the nonparametric Mann-Whitney U test or 2-way ANOVA with Bonferroni’s post hoc tests. *P < 0.05, **P < 0.01 versus control PA-SMCs and versus control PA-SMCs at 0 minutes; #P < 0.05, ##P < 0.01 versus iPAH PA-SMCs at 0 minutes.