Rao Rashmi J, Yang Jimin, Jiang Siyi, El-Khoury Wadih, Hafeez Neha, Okawa Satoshi, Tai Yi Yin, Tang Ying, Aaraj Yassmin Al, Sembrat John C, Chan Stephen Y
Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States.
Department of Molecular Biology, Jeonbuk National University, Jeonju, South Korea.
Am J Physiol Lung Cell Mol Physiol. 2025 Jan 1;328(1):L148-L158. doi: 10.1152/ajplung.00048.2024. Epub 2024 Dec 10.
Pulmonary arterial hypertension (PAH) is a progressive disease driven by endothelial cell inflammation and dysfunction, resulting in the pathological remodeling of the pulmonary vasculature. Innate immune activation has been linked to PAH development; however, the regulation, propagation, and reversibility of the induction of inflammation in PAH are poorly understood. Here, we demonstrate the role of interferon-inducible protein 16 (IFI16), an innate immune sensor, as a modulator of endothelial inflammation in pulmonary hypertension, using human pulmonary artery endothelial cells (PAECs). Inflammatory stimulus of PAECs with IL-1β upregulates expression, inducing proinflammatory cytokine upregulation and cellular apoptosis. mRNA stability is regulated by post-transcriptional m6A modification, mediated by Wilms' tumor 1-associated protein (WTAP), a structural stabilizer of the methyltransferase complex, via regulation of m6A methylation of . In addition, m6A levels are increased in the peripheral blood mononuclear cells of patients with PAH compared with control, indicating that quantifying this epigenetic change in patients may hold potential as a biomarker for disease identification. In summary, our study demonstrates that IFI16 mediates inflammatory endothelial pathophenotypes seen in pulmonary arterial hypertension. Our work establishes a paradigm of the regulatory role of the Wilms' tumor 1-associated protein (WTAP)-interferon inducible protein 16 (IFI16) axis that uses m6A RNA methylation to drive endothelial inflammatory activation in pulmonary hypertension. Consequently, because m6A epigenetic modifications are both reversible and dynamic, this axis is an attractive diagnostic and therapeutic target in pulmonary hypertension and more broadly in endothelial immune activation.
肺动脉高压（PAH）是一种由内皮细胞炎症和功能障碍驱动的进行性疾病，导致肺血管系统的病理重塑。固有免疫激活与PAH的发展有关；然而，PAH中炎症诱导的调节、传播和可逆性仍知之甚少。在这里，我们使用人肺动脉内皮细胞（PAECs）证明了干扰素诱导蛋白16（IFI16）作为一种固有免疫传感器，在肺动脉高压中作为内皮炎症调节剂的作用。用IL-1β对PAECs进行炎症刺激会上调其表达，诱导促炎细胞因子上调和细胞凋亡。mRNA稳定性由转录后m6A修饰调节，该修饰由威尔姆斯瘤1相关蛋白（WTAP）介导，WTAP是甲基转移酶复合物的结构稳定剂，通过调节其m6A甲基化来实现。此外，与对照组相比，PAH患者外周血单核细胞中的m6A水平升高，这表明量化患者的这种表观遗传变化可能具有作为疾病识别生物标志物的潜力。总之，我们的研究表明IFI16介导了肺动脉高压中所见的炎症性内皮病理表型。我们的工作建立了威尔姆斯瘤1相关蛋白（WTAP）-干扰素诱导蛋白16（IFI16）轴调节作用的范式，该轴利用m6A RNA甲基化在肺动脉高压中驱动内皮炎症激活。因此，由于m6A表观遗传修饰既是可逆的又是动态的，该轴是肺动脉高压以及更广泛的内皮免疫激活中一个有吸引力的诊断和治疗靶点。
