Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension.
Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension.
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DOI：
10.1073/pnas.2023899118
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发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Nakaoka Y
中科院分区：
文献类型：
--
作者：
Masaki T;Okazawa M;Asano R;Inagaki T;Ishibashi T;Yamagishi A;Umeki-Mizushima S;Nishimura M;Manabe Y;Ishibashi-Ueda H;Shirai M;Tsuchimochi H;Pearson JT;Kumanogoh A;Sakata Y;Ogo T;Kishimoto T;Nakaoka Y
炎症信号被认为对PAH的发病机制至关重要;然而，其潜在机制在很大程度上仍不清楚。在这项研究中，我们证明了AHR对PAH的发病机制有因果关系，激活了肺部的局灶性炎症反应，促进了免疫细胞从骨髓中的浸润。此外，我们发现PAH患者血清中AHR激动活性较高的患者比活性较低的患者更容易发生严重的临床事件。由于以肺动脉血管舒张为靶点的肺动脉高压常规治疗对重度PAH的疗效有限，因此AHR信号通路代表了PAH的有希望的治疗靶点。此外，血清中的AHR激动活性代表PAH的生物标志物。肺动脉高压（PAH）是一种破坏性疾病，其特征在于小至中等大小的远端肺动脉中的动脉病变，通常伴有炎性细胞浸润。芳烃受体（AHR）是一种核受体/转录因子，可解毒外源性物质并调节各种免疫细胞的分化和功能。然而，AHR在PAH发病机制中的作用在很大程度上是未知的。在此，我们探讨AHR在PAH发病机制中的作用。PAH患者血清中AHR激动活性显著高于健康志愿者，且与PAH预后不良相关。用有效的内源性AHR激动剂6-甲酰吲哚并[3，2-B]咔唑联合缺氧处理的Sprague-Dawley大鼠出现严重的肺动脉高压（PH）伴丛状样病变，而用有效的血管内皮生长因子受体2抑制剂处理的Sprague-Dawley大鼠则没有。使用CRISPR/Cas9系统产生的Ahr敲除（Ahr−/−）大鼠在SU 5416/缺氧模型中没有出现PH。饮食中含有一种中草药青黛，结合缺氧导致Ahr+/+大鼠出现PH，但在Ahr−/−大鼠中没有。RNA-seq分析、染色质免疫沉淀（ChIP）-seq分析、免疫组织化学分析和骨髓移植实验表明，内皮细胞和外周血单核细胞中多种炎症信号通路的激活上调，导致CD 4 + IL-21+ T细胞和MRC 1+巨噬细胞以AHR依赖性方式浸润到血管病变中。总之，AHR在PAH的发生和发展中起着至关重要的作用，并且AHR信号通路代表了PAH的有希望的治疗靶点。
Inflammatory signals are thought to be crucial for the pathogenesis of PAH; however, the underlying mechanism is still largely unknown. In this study, we demonstrate that AHR makes a causal contribution to the pathogenesis of PAH, activating a focal inflammatory response in the lungs and promoting infiltration of immune cells from the bone marrow. Furthermore, we found that PAH patients with higher AHR agonistic activity in sera are more susceptible to severe clinical events than those with lower activity. Because conventional therapy for pulmonary hypertension targeting pulmonary artery vasodilation has limited efficacy against severe PAH, the AHR-signaling pathway represents a promising therapeutic target for PAH. In addition, AHR agonistic activity in serum represents a biomarker for PAH. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague–Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague–Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr−/−) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr−/− rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
27.4
作者：
Nakaoka Y;Isobe M;Takei S;Tanaka Y;Ishii T;Yokota S;Nomura A;Yoshida S;Nishimoto N
通讯作者：
Nishimoto N
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
在接受青-DAI治疗的患者（中草药）中的肺动脉高压发育。
DOI：
10.2169/internalmedicine.1523-18
发表时间：
2019-02-01
期刊：
Internal medicine (Tokyo, Japan)
影响因子：
--
作者：
Misumi K;Ogo T;Ueda J;Tsuji A;Fukui S;Konagai N;Asano R;Yasuda S
通讯作者：
Yasuda S
影响因子：
3.7
作者：
Mezrich JD;Nguyen LP;Kennedy G;Nukaya M;Fechner JH;Zhang X;Xing Y;Bradfield CA
通讯作者：
Bradfield CA