Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge CB23 8RE, UK.
Nat Commun. 2017 Jan 13;8:14079. doi: 10.1038/ncomms14079.
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.
骨形成蛋白受体 II 型（BMPR-II）基因的杂合胚系突变是遗传性肺动脉高压（HPAH）的基础。尽管炎症会促进 PAH，但炎症和 BMPR-II 功能障碍协同导致疾病的机制仍不清楚。在这里，我们发现肿瘤坏死因子-α（TNFα）选择性地降低肺动脉平滑肌细胞（PASMC）中 BMPR-II 的转录，并通过 ADAM10 和 ADAM17 介导 BMPR-II 的翻译后切割。TNFα 介导的 BMPR-II 抑制会破坏 BMP 信号转导，导致 BMP6 通过优先激活 ALK2/ACTR-IIA 信号轴引起 PASMC 增殖。此外，TNFα 通过 SRC 家族激酶增加具有降低的 BMPR-II 表达的 HPAH PASMC 中的促增殖 NOTCH2 信号。我们在 PAH 的啮齿动物模型中证实了这种信号转换，并证明抗 TNFα 免疫疗法可逆转疾病进展，恢复正常的 BMP/NOTCH 信号。总之，这些发现确定了 BMP 和 TNFα 信号在疾病中的作用机制，并为 PAH 的治疗干预提供了一种可行的方法。
