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.
View: Text | PDF
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

×

Figure 2

rHuIL-6 exaggerates the apoptosis-resistant phenotype in iPAH PA-SMCs.

Options: View larger image (or click on image) Download as PowerPoint
rHuIL-6 exaggerates the apoptosis-resistant phenotype in iPAH PA-SMCs. (...
(A) Caspase-3/7 activity in PA-SMCs derived from control and iPAH patients following staurosporine, cycloheximide, or TNF-α treatment in the presence or absence of rHuIL-6 (n = 7–8). (B) Representative TUNEL images and quantification of the percentage of TUNEL-positive cells (arrowheads) in control and iPAH PA-SMCs exposed to staurosporine in the presence or absence of rHuIL-6 (n = 4). (C) Representative Western blots and quantification of MCL-1/β-actin and BCL2/Bax ratios in human PA-SMCs derived from control and iPAH at different time points following exposure to rHuIL-6 (n = 5–9). Scale bars: 50 μm. Data are presented as mean ± SEM. Comparisons were made using 2-way ANOVA with Bonferroni’s post hoc tests. *P < 0.05, **P < 0.01, ***P < 0.001; ****P < 0.0001 versus PA-SMCs under basal conditions or untreated in controls and iPAH; #P < 0.05, ####P < 0.0001 versus different treatments in iPAH PA-SMCs. RFU, relative fluorescence units.