Journal Article

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

Nikolic, Marko Z., Herrera, Blanca, Bradley, John R., Upton, Paul D., Al-Lamki, Rafia, Morrell, Nicholas W., Southwood, Mark, Crosby, Alexi, Yang, Xudong, Hurst, Liam A., Deighton, John, Dunmore, Benjamin J., Long, Lu, Inman, Gareth J., Rana, Amer A.

2017

Overview

Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNFα-mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2/ACTR-IIA signalling axis. Furthermore, TNFα, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNFα immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNFα signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH. Reduced BMP receptor II signalling underlies pulmonary arterial hypertension (PAH). Here, Hurst et al . show that TNFα subverts BMP signalling by increasing BMP6 expression and signalling via an alternative BMP receptor, ALK2, in pulmonary artery smooth muscle cells to drive abnormal proliferation and PAH.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 14/19 / 42/89 / 631/80/86/2370 / 64/60 / 692/420/256/2515 / 692/699/75/243 / 82/29 / 82/80 / 96/106 / 96/109 / 96/21 / ADAM10 Protein - genetics / ADAM10 Protein - metabolism / Animals / Bone Morphogenetic Protein 6 - metabolism / Bone Morphogenetic Protein Receptors, Type II - genetics / Bone Morphogenetic Protein Receptors, Type II - metabolism / Familial Primary Pulmonary Hypertension - genetics / Familial Primary Pulmonary Hypertension - metabolism / Female / Humanities and Social Sciences / Humans / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Myocytes, Smooth Muscle - metabolism / Pulmonary Artery - metabolism / Rats / Receptor, Notch2 - genetics / Receptor, Notch2 - metabolism / Receptor, Notch3 - genetics / Receptor, Notch3 - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism