TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.
TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.
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DOI：
10.1038/ncomms14079
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发表时间：
2017-01-13
影响因子：
16.6
通讯作者：
Morrell NW
中科院分区：
文献类型：
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作者：
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
骨形态发生蛋白II型受体（BMPR-II）基因的杂合生殖系突变是遗传性肺动脉高压（HPAH）的基础。虽然炎症促进PAH，但炎症和BMPR-II功能障碍共同导致疾病的机制仍不清楚。在此，我们发现肿瘤坏死因子-α（TNFα）选择性地减少BMPR-II的转录，并通过脱落酶，ADAM 10和ADAM 17介导的翻译后BMPR-II切割在肺动脉平滑肌细胞（PASMCs）。TNFα介导的BMPR-II抑制破坏BMP信号传导，通过优先激活ALK 2/ACTR-IIA信号传导轴导致BMP 6介导的PASMC增殖。此外，TNFα通过SRC家族激酶增加HPAH PASMC中促增殖NOTCH 2信号传导，同时降低BMPR-II表达。我们在PAH啮齿动物模型中证实了这种信号转换，并证明抗TNF α免疫治疗逆转了疾病进展，恢复了正常的BMP/NOTCH信号传导。总之，这些发现确定了BMP和TNFα信号传导促进疾病的机制，并提出了PAH治疗干预的易处理方法。BMP受体II信号传导减少是肺动脉高压（PAH）的基础。Hurst等人在本文中表明，TNFα通过增加肺动脉平滑肌细胞中BMP 6的表达和通过替代BMP受体ALK 2的信号传导来破坏BMP信号传导，从而驱动异常增殖和PAH。
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. Reduced BMP receptor II signalling underlies pulmonary arterial hypertension (PAH). Here, Hurst et al. show that TNFα subverts BMP signalling by increasing BMP6 expression and signalling via an alternative BMP receptor, ALK2, in pulmonary artery smooth muscle cells to drive abnormal proliferation and PAH.