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; Nicholas W. Morrell

doi:10.1038/ncomms14079

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 language	English
Article number	14079
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14079
Publication status	Published - 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. Article 14079. https://doi.org/10.1038/ncomms14079

@article{44c54b3111ac4423913df4e3d0f31507,

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.",

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

note = "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.",

year = "2017",

month = jan,

day = "13",

doi = "10.1038/ncomms14079",

language = "English",

volume = "8",

pages = "1--14",

journal = "Nature Communications",

issn = "2041-1723",

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Hurst, LA, Dunmore, BJ, Long, L, Crosby, A, Al-Lamki, R, Deighton, J, Southwood, M, Yang, X, Nikolic, MZ, Herrera, B, Inman, GJ, Bradley, JR, Rana, AA, Upton, PD & Morrell, NW 2017, 'TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling', Nature Communications, vol. 8, 14079, pp. 1-14. https://doi.org/10.1038/ncomms14079

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 -

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

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