Key Points Ly6Clo nonclassical monocytes infiltrate the pulmonary vasculature and promote PH. Hif1α regulates the maturation of nonclassical monocytes into infiltrating IMØ. Infiltrating IMØ promote PH by modulating local immune and cytokine responses. An increasing body of evidence suggests that bone marrow–derived myeloid cells play a critical role in the pathophysiology of pulmonary hypertension (PH). However, the true requirement for myeloid cells in PH development has not been demonstrated, and a specific disease-promoting myeloid cell population has not been identified. Using bone marrow chimeras, lineage labeling, and proliferation studies, we determined that, in murine hypoxia-induced PH, Ly6Clo nonclassical monocytes are recruited to small pulmonary arteries and differentiate into pulmonary interstitial macrophages. Accumulation of these nonclassical monocyte–derived pulmonary interstitial macrophages around pulmonary vasculature is associated with increased muscularization of small pulmonary arteries and disease severity. To determine if the sensing of hypoxia by nonclassical monocytes contributes to the development of PH, mice lacking expression of hypoxia-inducible factor-1α in the Ly6Clo monocyte lineage were exposed to hypoxia. In these mice, vascular remodeling and PH severity were significantly reduced. Transcriptome analyses suggest that the Ly6Clo monocyte lineage regulates PH through complement, phagocytosis, Ag presentation, and chemokine/cytokine pathways. Consistent with these murine findings, relative to controls, lungs from pulmonary arterial hypertension patients displayed a significant increase in the frequency of nonclassical monocytes. Taken together, these findings show that, in response to hypoxia, nonclassical monocytes in the lung sense hypoxia, infiltrate small pulmonary arteries, and promote vascular remodeling and development of PH. Our results demonstrate that myeloid cells, specifically cells of the nonclassical monocyte lineage, play a direct role in the pathogenesis of PH.

中文翻译：

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非经典单核细胞感知缺氧，调节肺血管重构，促进肺动脉高压

要点 Ly6Clo 非经典单核细胞浸润肺血管系统并促进 PH。Hif1α 调节非经典单核细胞成熟为浸润性 IMØ。浸润 IMØ 通过调节局部免疫和细胞因子反应来促进 PH。越来越多的证据表明，骨髓来源的髓样细胞在肺动脉高压 (PH) 的病理生理学中起关键作用。然而，尚未证明 PH 发展对髓样细胞的真正需求，并且尚未确定特定的促进疾病的髓样细胞群。使用骨髓嵌合体、谱系标记和增殖研究，我们确定，在小鼠缺氧诱导的 PH 中，Ly6Clo 非经典单核细胞被募集到小肺动脉并分化为肺间质巨噬细胞。这些非经典单核细胞衍生的肺间质巨噬细胞在肺血管周围的积累与小肺动脉的肌肉化增加和疾病严重程度有关。为了确定非经典单核细胞对缺氧的感知是否有助于 PH 的发展，将 Ly6Clo 单核细胞谱系中缺乏缺氧诱导因子-1α 表达的小鼠暴露于缺氧环境中。在这些小鼠中，血管重塑和 PH 严重程度显着降低。转录组分析表明，Ly6Clo 单核细胞谱系通过补体、吞噬作用、Ag 呈递和趋化因子/细胞因子途径调节 PH。与这些小鼠的发现一致，相对于对照，肺动脉高压患者的肺显示非经典单核细胞的频率显着增加。综上所述，这些发现表明，响应缺氧，肺中的非经典单核细胞感知缺氧，浸润小肺动脉，促进血管重塑和 PH 的发展。我们的结果表明骨髓细胞，特别是非经典单核细胞谱系的细胞，在 PH 的发病机制中起直接作用。