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

Liam A. Hurst, Benjamin J. Dunmore, Lu Long, Alexi Crosby, Rafia Al-Lamki, John Deighton, Mark Southwood, Xudong Yang, Marko Z. Nikolic, Blanca Herrera, Gareth J. Inman, John R. Bradley, Amer A. Rana, Paul D. Upton () and Nicholas W. Morrell ()
Additional contact information
Liam A. Hurst: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Benjamin J. Dunmore: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Lu Long: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Alexi Crosby: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Rafia Al-Lamki: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
John Deighton: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Mark Southwood: Papworth Hospital, Papworth Everard
Xudong Yang: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Marko Z. Nikolic: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Blanca Herrera: Facultad de Farmacia, Universidad Complutense. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Del Prof Martin Lagos
Gareth J. Inman: Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital And Medical School
John R. Bradley: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Amer A. Rana: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Paul D. Upton: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals
Nicholas W. Morrell: Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14079

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