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

TY - JOUR

T1 - TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

AU - Hurst, Liam A.

AU - Dunmore, Benjamin J.

AU - Long, Lu

AU - Crosby, Alexi

AU - Al-Lamki, Rafia

AU - Deighton, John

AU - Southwood, Mark

AU - Yang, Xudong

AU - Nikolic, Marko Z.

AU - Herrera, Blanca

AU - Inman, Gareth J.

AU - Bradley, John R.

AU - Rana, Amer A.

AU - Upton, Paul D.

AU - Morrell, Nicholas W.

N1 - This work was supported by grants from the British Heart Foundation, RG/13/4/30107 (N.W.M.), CH/09/001/25945 (N.W.M.), a Medical Research Council Experimental Challenge Award (N.W.M.), a Fondation Leducq Transatlantic Network of Excellence (N.W.M.), the Dinosaur Trust (A.R.) and a UK National Institute for Health Research Healthcare Science Fellowship (M.S.). L.A.H. was funded through a BHF PhD student programme (FS/09/050). The UK National Institute for Health Research Cambridge Biomedical Research Centre and Cell Phenotyping Hub provided infrastructure support.

PY - 2017/1/13

Y1 - 2017/1/13

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms14079

DO - 10.1038/ncomms14079

M3 - Article

C2 - 28084316

SN - 2041-1723

VL - 8

SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

M1 - 14079

ER -