title: TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.
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.
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Liam A
authors.initials: LA
authors.lastname: Hurst
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dunmore
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Long
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Rafia
authors.initials: R
authors.lastname: Al-Lamki
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Deighton
authors.affiliation: Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge CB23 8RE, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Xudong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Marko Z
authors.initials: MZ
authors.lastname: Nikolic
authors.affiliation: Department Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Del Prof Martin Lagos, Madrid 28040, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Herrera
authors.affiliation: Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital And Medical School, Dundee DD1 9SY, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Inman
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Bradley
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Amer A
authors.initials: AA
authors.lastname: Rana
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Paul D
authors.identifier: 0000-0003-2716-4921
authors.initials: PD
authors.lastname: Upton
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D055418:Bone Morphogenetic Protein 6; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D014409:Tumor Necrosis Factor-alpha; D052006:Bone Morphogenetic Protein Receptors, Type II; D000072197:ADAM10 Protein