BACKGROUND The infiltration of macrophages into the lungs is a common characteristic of perivascular inflammation, contributing to vascular remodeling in pulmonary hypertension (PH). Peli1 (pellino E3 ubiquitin-protein ligase 1) plays a critical role in regulating the production of proinflammatory cytokines and the polarization of macrophages in various diseases. However, the role of Peli1 in PH remains to be investigated. METHODS The expression and biological function of Peli1 were investigated in both human and experimental models of PH. Peli1-deficient mice and bone marrow transplant mice were utilized to explore the roles of Peli1 in macrophages in vivo. Proteomic analysis and molecular biology techniques were used to uncover the underlying mechanisms. RESULTS The upregulation of Peli1 in the lungs and alveolar macrophages was observed in hypoxia-treated mice. Peli1 knockout mice and myeloid Peli1-deficient mice significantly ameliorated hypoxia-induced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Mechanistically, Peli1 facilitated the ubiquitination and subsequent proteasomal degradation of Foxp1 (forkhead box p1), thereby alleviating its suppression of IL (interleukin)-6 transcription and contributing to macrophage activation. Furthermore, myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in hypoxia-induced PH mice. CONCLUSIONS Our findings demonstrate that the Peli1-Foxp1-IL-6 pathway plays a crucial role in macrophage activation and recruitment during the development of PH, underscoring the potential of Peli1 as a therapeutic target for PH.

中文翻译：

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巨噬细胞中的 Peli1 缺陷通过增强 Foxp1 介导的 IL-6 转录抑制来减轻肺动脉高压。


背景 巨噬细胞浸润到肺部是血管周围炎症的常见特征，有助于肺动脉高压 （PH） 的血管重塑。Peli1 （pellino E3 泛素-蛋白连接酶 1） 在各种疾病中调节促炎细胞因子的产生和巨噬细胞的极化中起关键作用。然而，Peli1 在 PH 中的作用仍有待研究。方法 在 PH 人类和实验模型中研究 Peli1 的表达和生物学功能，利用 Peli1 缺陷小鼠和骨髓移植小鼠探讨 Peli1 在体内巨噬细胞中的作用。使用蛋白质组学分析和分子生物学技术来揭示潜在机制。结果 在缺氧治疗的小鼠中观察到肺和肺泡巨噬细胞中 Peli1 的上调。Peli1 敲除小鼠和髓系 Peli1 缺陷小鼠显著改善缺氧诱导的右心室收缩压、右心室肥大和肺血管重塑。从机制上讲，Peli1 促进了 Foxp1 （叉头盒 p1） 的泛素化和随后的蛋白酶体降解，从而减轻了其对 IL （白细胞介素）-6 转录的抑制并有助于巨噬细胞活化。此外，髓系 Foxp1 缺陷部分消除了髓系 Peli1 缺陷对缺氧诱导的 PH 小鼠的保护作用。结论我们的研究结果表明，Peli1-Foxp1-IL-6 通路在 PH 发展过程中巨噬细胞活化和募集中起关键作用，强调了 Peli1 作为 PH 治疗靶点的潜力。