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 (Lead / Corresponding author), Nicholas W. Morrell (Lead / Corresponding author)

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    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.

    Original languageEnglish
    Article number14079
    Pages (from-to)1-14
    Number of pages14
    JournalNature Communications
    Volume8
    DOIs
    Publication statusPublished - 13 Jan 2017

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    Hurst, L. A., Dunmore, B. J., Long, L., Crosby, A., Al-Lamki, R., Deighton, J., Southwood, M., Yang, X., Nikolic, M. Z., Herrera, B., Inman, G. J., Bradley, J. R., Rana, A. A., Upton, P. D., & Morrell, N. W. (2017). TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nature Communications, 8, 1-14. [14079]. https://doi.org/10.1038/ncomms14079