Dysregulated retinoic acid signaling in airway smooth muscle cells in asthma.
Dysregulated retinoic acid signaling in airway smooth muscle cells in asthma.
复制标题
DOI：
10.1096/fj.202100835r
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
维生素 A 缺乏已被证明会加剧过敏性哮喘。先前的研究假设，视黄酸 (RA) 是维生素 A 的活性代谢物和 RA 受体 (RAR) 的高亲和力配体，在气道炎症状态下会减少，并导致哮喘的多种特征，包括气道高反应性和气道平滑肌 (ASM) 细胞过度积累。在这项研究中，我们直接量化了 RA，并检查了从哮喘供体获得的肺和 ASM 细胞以及过敏原攻击小鼠的肺中 RA 水平降低和 RA 介导的信号传导的分子基础。与非哮喘人类肺和 PBS 攻击小鼠相比，哮喘供体和屋尘螨 (HDM) 攻击小鼠的肺组织中 RA 和视黄醇水平分别显着降低。 mRNA 和蛋白表达的定量显示，RA 生物合成第一步中的失调与 RA 的减少一致，包括哮喘肺中视黄醇脱氢酶 (RDH)-10 的蛋白表达减少以及 RDH11 和脱氢酶/还原酶 (DHRS)-4 的蛋白表达增加。非哮喘和哮喘肺的蛋白质组学分析也显示 AP-1 靶标的蛋白质表达发生显着变化，与 AP-1 活性增加一致。此外，哮喘人类 ASM 细胞中 RA 基础水平和 RA 生物合成能力均降低。用全反式 RA (ATRA) 或 RARγ 特异性激动剂 (CD1530) 处理人 ASM 细胞，可抑制有丝分裂原诱导的细胞增殖和 AP-1 依赖性转录。这些数据表明，哮喘肺部的 RA 代谢降低，并且使用 ATRA 或 RARγ 激动剂增强 RAR 信号传导可能会减轻与哮喘相关的气道重塑。
Vitamin A deficiency has been shown to exacerbate allergic asthma. Previous studies have postulated that retinoic acid (RA), an active metabolite of vitamin A and high-affinity ligand for RA receptor (RAR), is reduced in airway inflammatory condition and contributes to multiple features of asthma including airway hyperresponsiveness and excessive accumulation of airway smooth muscle (ASM) cells. In this study, we directly quantified RA and examined the molecular basis for reduced RA levels and RA-mediated signaling in lungs and ASM cells obtained from asthmatic donors and in lungs from allergen-challenged mice. Levels of RA and retinol were significantly lower in lung tissues from asthmatic donors and house dust mite (HDM)-challenged mice compared to non-asthmatic human lungs and PBS-challenged mice, respectively. Quantification of mRNA and protein expression revealed dysregulation in the first step of RA biosynthesis consistent with reduced RA including decreased protein expression of retinol dehydrogenase (RDH)-10 and increased protein expression of RDH11 and dehydrogenase/reductase (DHRS)-4 in asthmatic lung. Proteomic profiling of non-asthmatic and asthmatic lungs also showed significant changes in the protein expression of AP-1 targets consistent with increased AP-1 activity. Further, basal RA levels and RA biosynthetic capabilities were decreased in asthmatic human ASM cells. Treatment of human ASM cells with all-trans RA (ATRA) or the RARγ-specific agonist (CD1530) resulted in the inhibition of mitogen-induced cell proliferation and AP-1-dependent transcription. These data suggest that RA metabolism is decreased in asthmatic lung and that enhancing RAR signaling using ATRA or RARγ agonists may mitigate airway remodeling associated with asthma.