TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling
Authors
Hurst, LA
Dunmore, Benjamin
Long, Lu
Crosby, A
Al-Lamki, Rafia
Deighton, J
Southwood, M
Yang, XuDong
Herrera, B
Inman, GJ
Publication Date
2017-01-13Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Nature Publishing Group
Volume
8
Number
14079
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Hurst, L., Dunmore, B., Long, L., Crosby, A., Al-Lamki, R., Deighton, J., Southwood, M., et al. (2017). TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nature Communications, 8 (14079)https://doi.org/10.1038/ncomms14079
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.
Sponsorship
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.
Funder references
MRC (MR/K020919/1)
British Heart Foundation (RG/13/4/30107)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Dinosaur Trust (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
British Heart Foundation (PG/14/31/30786)
British Heart Foundation (CH/09/001/25945)
British Heart Foundation (PG/13/91/30579)
British Heart Foundation (SP/12/12/29836)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/ncomms14079
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262664
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International