Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension
Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension
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DOI：
10.1073/pnas.1424774112
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发表时间：
2015-05-19
影响因子：
11.1
通讯作者：
Nakaoka, Yoshikazu
中科院分区：
文献类型：
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作者：
Hashimoto-Kataoka, Takahiro;Hosen, Naoki;Nakaoka, Yoshikazu
IL-6是一种多功能促炎细胞因子，在肺动脉高压（PAH）患者血清中升高，可预测特发性PAH（IPAH）患者的生存期。先前的动物实验和临床人类研究表明，IL-6在PAH中是重要的;然而，IL-6介导的PAH发病机制的分子机制一直是难以捉摸的。在这里，我们确定了IL-21作为PAH中IL-6信号传导的下游靶标。首先，我们发现通过单克隆抗IL-6受体抗体MR 16 -1阻断IL-6可改善低氧诱导的肺动脉高压（HPH），并防止低氧诱导的Th 17细胞和M2巨噬细胞在肺中的积聚。一致地，IL-17和IL-21基因（Th 17细胞的特征基因之一）的表达水平在缺氧暴露后在用对照抗体处理的小鼠的肺中显著上调，但在用MR 16 -1处理的小鼠的肺中未显著上调。尽管用抗IL-17 A中和抗体阻断IL-17对HPH没有影响，但IL-21受体缺陷小鼠对HPH具有抗性，并且在肺中没有表现出M2巨噬细胞的显著积聚。根据这些发现，IL-21促进初级肺泡巨噬细胞向M2表型极化。值得注意的是，在接受肺移植的IPAH患者的肺中检测到IL-21和M2巨噬细胞标志物的显著增强的表达。总的来说，这些发现表明IL-21促进PAH与IL-6信号传导下游的M2巨噬细胞极化相关。IL-6/IL-21信号轴可能是治疗PAH的潜在靶点。
IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.