15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.
15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.
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15LO1指示哮喘呼吸道上皮细胞谷胱甘肽氧化还原改变，从而加重2型炎症。
DOI：
10.1172/jci151685
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发表时间：
2022-01-04
期刊：
影响因子：
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通讯作者：
Wenzel SE
中科院分区：
文献类型：
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作者：
Nagasaki T;Schuyler AJ;Zhao J;Samovich SN;Yamada K;Deng Y;Ginebaugh SP;Christenson SA;Woodruff PG;Fahy JV;Trudeau JB;Stoyanovsky D;Ray A;Tyurina YY;Kagan VE;Wenzel SE
改变的氧化还原生物学挑战所有细胞，补偿反应通常决定细胞的命运。当15脂氧合酶1（15 LO 1）（一种在哮喘人气道上皮细胞（HAEC）中丰富的脂质过氧化酶）结合磷脂酰乙醇胺结合蛋白1（PEBP 1）时，产生氢过氧磷脂，其驱动亚铁凋亡细胞死亡。过氧化物酶，包括谷胱甘肽过氧化物酶4（GPX 4），代谢氢过氧磷脂羟基衍生物，以防止铁中毒死亡，但消耗还原型谷胱甘肽（GSH）。胱氨酸转运蛋白SLC 7A 11关键地恢复/维持细胞内GSH。我们假设，高15 LO 1，PEBP 1和GPX 4活性驱动异常哮喘氧化还原生物学，通过降低支气管肺泡灌洗液（BAL）和上皮内细胞GSH：氧化型GSH（GSSG）比率证明，以增强2型（T2）炎症反应。在哮喘和健康对照（HC）细胞和液体中测量GSH、GSSG（酶测定）、15 L01、GPX 4、SLC 7A 11和T2生物标志物（Western印迹和RNA-Seq），适当时使用siRNA敲低。与HC BAL液相比，哮喘组GSSG升高，GSH：GSSG降低，而细胞内GSH降低。在体外，T2细胞因子（IL-13）诱导15 LO 1产生过氧化氢磷脂，降低细胞内GSH和增加细胞外GSSG。通过抑制SLC 7A 11进一步降低GSH可增强T2炎性蛋白表达和铁凋亡。离体，氧化还原失衡对应于15 L01和SLC 7A 11表达、T2生物标志物和恶化的临床结果。因此，15 L01途径诱导的氧化还原生物学扰动使T2炎症和哮喘控制恶化，支持15 L01作为治疗靶点。
Altered redox biology challenges all cells, with compensatory responses often determining a cell’s fate. When 15 lipoxygenase 1 (15LO1), a lipid-peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine-binding protein 1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase 4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter SLC7A11 critically restores/maintains intracellular GSH. We hypothesized that high 15LO1, PEBP1, and GPX4 activity drives abnormal asthmatic redox biology, evidenced by lower bronchoalveolar lavage (BAL) fluid and intraepithelial cell GSH:oxidized GSH (GSSG) ratios, to enhance type 2 (T2) inflammatory responses. GSH, GSSG (enzymatic assays), 15LO1, GPX4, SLC7A11, and T2 biomarkers (Western blot and RNA-Seq) were measured in asthmatic and healthy control (HC) cells and fluids, with siRNA knockdown as appropriate. GSSG was higher and GSH:GSSG lower in asthmatic compared with HC BAL fluid, while intracellular GSH was lower in asthma. In vitro, a T2 cytokine (IL-13) induced 15LO1 generation of hydroperoxy-phospholipids, which lowered intracellular GSH and increased extracellular GSSG. Lowering GSH further by inhibiting SLC7A11 enhanced T2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances corresponded to 15LO1 and SLC7A11 expression, T2 biomarkers, and worsened clinical outcomes. Thus, 15LO1 pathway–induced redox biology perturbations worsen T2 inflammation and asthma control, supporting 15LO1 as a therapeutic target.