Departments of Biomedical and Molecular Sciences, Medicine, and Surgery, Queen's University Kingston , Ontario , Canada.
Department of Medicine, University of Cambridge, Cambridge , United Kingdom.
Am J Physiol Lung Cell Mol Physiol. 2018 Dec 1;315(6):L977-L990. doi: 10.1152/ajplung.00477.2017. Epub 2018 Sep 20.
Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3 mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.
自然杀伤 (NK) 细胞是具有细胞毒性的先天淋巴细胞，在妊娠和癌症中调节血管结构方面发挥着重要作用。在肺动脉高压 (PAH) 患者以及多种疾病的啮齿动物模型中，已经发现 NK 细胞功能受损。然而，NK 细胞功能障碍对 PAH 的起始和进展的确切贡献仍然未知。在这里，我们报告了两种独立的 NK 细胞功能障碍遗传模型中自发性肺动脉高压的发展，包括由于 NFIL3 转录因子缺失而导致 NK 细胞缺乏的 Nfil3 小鼠，以及缺乏 NK 激活受体 NKp46 的 Ncr1-Gfp 小鼠。NK 不足的小鼠模型表现出右心室收缩压升高和肺动脉肌化，而左心室舒张末期压没有升高，表明肺动脉高压的发展不是继发于左心功能障碍。在严重的 NK 细胞损伤或缺失的情况下，一部分小鼠未能发展为肺动脉高压，而是表现出全身血压降低，表明血管异常不仅局限于肺循环，还延伸至全身血管。在这两种小鼠模型中，PAH 的发展与白细胞介素-23 产生的升高有关，而 Ncr1-Gfp 小鼠的全身低血压伴随着血管生成素-2 的丧失。总之，这些结果支持 NK 细胞在调节肺和全身血管功能以及 PAH 发病机制中的重要作用。
