Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages
Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages
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Regnase-1 通过降解肺泡巨噬细胞中白细胞介素 6 和血小板衍生生长因子的 mRNA 来预防肺动脉高压
DOI：
10.1161/circulationaha.122.059435
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发表时间：
2022
期刊：
影响因子：
37.8
通讯作者：
Ishi
中科院分区：
文献类型：
--
作者：
Yaku Ai;Inagaki Tadakatsu;Asano Ryotaro;Okazawa Makoto;Mori Hiroyoshi;Sato Ayuko;Hia Fabian;Masaki Takeshi;Manabe Yusuke;Ishibashi Tomohiko;Vandenbon Alexis;Nakatsuka Yoshinari;Akaki Kotaro;Yoshinaga Masanori;Uehata Takuya;Mino Takashi;Morita Satoshi;Ishi
背景肺动脉高压（pulmonary arterial hypertension，PAH）是一种以闭塞性肺血管重构为特征的肺动脉高压（pulmonary hypertension，PH），可导致右心衰竭。虽然PAH的发病机制尚未完全清楚，但已显示炎症反应和细胞因子与PAH相关，特别是与结缔组织病-PAH相关。在这个意义上说，Regnase-1，一种RNA酶，调节基因编码的免疫反应相关的基因，进行了调查，在有关的发病机制的PH。MethodsWe首先检查的表达水平ofZC 3 H12 A（编码Regnase-1）在外周血单核细胞从PH患者分类下的各种类型的PH，寻找theZC 3 H12 A的表达和临床特征之间的关联。然后，我们产生了骨髓细胞（包括肺泡巨噬细胞）中缺乏Regnase-1的小鼠，并检查了右心室收缩压和肺组织学变化。结果外周血单个核细胞中ZC 3 H12 A的表达与肺动脉高压患者的预后和疾病严重程度呈负相关，尤其是在结缔组织病-PAH中。Regnase-1在控制PAH中的关键作用也通过对肺泡巨噬细胞中缺乏Regnase-1的小鼠的分析得到加强。这些小鼠自发发生重度PAH，其特征为右心室收缩压升高和不可逆的肺血管重构，这概括了PAH患者的病理学。对这些PAH小鼠的肺泡巨噬细胞和肺动脉的转录组学分析显示，IL 6、IL 1b和Pdgfa/bare肺泡巨噬细胞中Regnase-1的潜在靶点在PAH的调节中。IL-6（白细胞介素-6）的抑制由抗IL-6受体抗体或血小板衍生的生长因子伊马替尼，但不是IL-1β（白细胞介素-1 β）由阿那白滞素，改善PAH的发病机制。结论Regnase-1通过控制肺泡巨噬细胞中的IL-6和血小板衍生的生长因子，维持肺先天免疫稳态，从而抑制小鼠PAH的发展。此外，Regnase-1在各种类型PH中的表达降低暗示其参与PH发病机制，并可作为疾病生物标志物，以及PH的治疗靶点。
BackgroundPulmonary arterial hypertension (PAH) is a type of pulmonary hypertension (PH) characterized by obliterative pulmonary vascular remodeling, resulting in right-sided heart failure. Although the pathogenesis of PAH is not fully understood, inflammatory responses and cytokines have been shown to be associated with PAH, in particular, with connective tissue disease-PAH. In this sense, Regnase-1, an RNase that regulates mRNAs encoding genes related to immune reactions, was investigated in relation to the pathogenesis of PH.MethodsWe first examined the expression levels ofZC3H12A(encoding Regnase-1) in peripheral blood mononuclear cells from patients with PH classified under various types of PH, searching for an association between theZC3H12Aexpression and clinical features. We then generated mice lacking Regnase-1 in myeloid cells, including alveolar macrophages, and examined right ventricular systolic pressures and histological changes in the lung. We further performed a comprehensive analysis of the transcriptome of alveolar macrophages and pulmonary arteries to identify genes regulated by Regnase-1 in alveolar macrophages.ResultsZC3H12Aexpression in peripheral blood mononuclear cells was inversely correlated with the prognosis and severity of disease in patients with PH, in particular, in connective tissue disease-PAH. The critical role of Regnase-1 in controlling PAH was also reinforced by the analysis of mice lacking Regnase-1 in alveolar macrophages. These mice spontaneously developed severe PAH, characterized by the elevated right ventricular systolic pressures and irreversible pulmonary vascular remodeling, which recapitulated the pathology of patients with PAH. Transcriptomic analysis of alveolar macrophages and pulmonary arteries of these PAH mice revealed thatIl6, Il1b, andPdgfa/bare potential targets of Regnase-1 in alveolar macrophages in the regulation of PAH. The inhibition of IL-6 (interleukin-6) by an anti–IL-6 receptor antibody or platelet-derived growth factor by imatinib but not IL-1β (interleukin-1β) by anakinra, ameliorated the pathogenesis of PAH.ConclusionsRegnase-1 maintains lung innate immune homeostasis through the control of IL-6 and platelet-derived growth factor in alveolar macrophages, thereby suppressing the development of PAH in mice. Furthermore, the decreased expression of Regnase-1 in various types of PH implies its involvement in PH pathogenesis and may serve as a disease biomarker, and a therapeutic target for PH as well.
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DOI：
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发表时间：
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Nat. Immunol
影响因子：
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影响因子：
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作者：
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平滑肌细胞中的 IL-6Ra 可预防血吸虫和缺氧引起的肺动脉高压。
DOI：
10.1165/rcmb.2018-0277le
发表时间：
2019
影响因子：
6.4
作者：
Mickael,Claudia;Kumar,Rahul;Hernandez-Saavedra,Daniel;Kassa,Biruk;Sanders,Linda;Koyanagi,Dan;Gu,Sue;Lee,MichaelH;Tuder,RubinM;Graham,BrianB
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