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Hurst, Liam A.; Dunmore, Benjamin J.; Long, Lu; Crosby, Alexi; Al-Lamki, Rafia; Deighton, John; Southwood, Mark; Yang, Xudong; Nikolic, Marko Z.; Herrera, Blanca; Inman, Gareth J.; Bradley, John R.; Rana, Amer A.; Upton, Paul D.; Morrell, Nicholas W.

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

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  • Media type: E-Article
  • Title: TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling
  • Contributor: Hurst, Liam A.; Dunmore, Benjamin J.; Long, Lu; Crosby, Alexi; Al-Lamki, Rafia; Deighton, John; Southwood, Mark; Yang, Xudong; Nikolic, Marko Z.; Herrera, Blanca; Inman, Gareth J.; Bradley, John R.; Rana, Amer A.; Upton, Paul D.; Morrell, Nicholas W.
  • imprint: Springer Science and Business Media LLC, 2017
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/ncomms14079
  • ISSN: 2041-1723
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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.</jats:p>
  • Access State: Open Access