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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & A, 2017. "TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14079
    DOI: 10.1038/ncomms14079
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    Cited by:

    1. Sokratis Kariotis & Emmanuel Jammeh & Emilia M. Swietlik & Josephine A. Pickworth & Christopher J. Rhodes & Pablo Otero & John Wharton & James Iremonger & Mark J. Dunning & Divya Pandya & Thomas S. Ma, 2021. "Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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