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

Hurst, L. A. et al. (2018) TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nature Communications, 8, 14079. (doi: 10.1038/ncomms14079) (PMID:28084316) (PMCID:PMC5241886)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by grants from the British Heart Foundation, RG/13/4/30107 (N.W.M.), CH/09/001/25945 (N.W.M.), a Medical Research Council Experimental Challenge Award (N.W.M.), a Fondation Leducq Transatlantic Network of Excellence (N.W.M.), the Dinosaur Trust (A.R.) and a UK National Institute for Health Research Healthcare Science Fellowship (M.S.). L.A.H. was funded through a BHF PhD student programme (FS/09/050). The UK National Institute for Health Research Cambridge Biomedical Research Centre and Cell Phenotyping Hub provided infrastructure support.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth
• Authors: Hurst, L. A., Dunmore, B. J., Long, L., Crosby, A., Al-Lamki, R., Deighton, J., Southwood, M., Yang, X., Nikolic, M. Z., Herrera, B., Inman, G. J., Bradley, J. R., Rana, A. A., Upton, P. D., and Morrell, N. W.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Nature Communications 8:14079
• Publisher Policy: Reproduced under a Creative Commons License