白细胞介素-27通过抑制脓毒症诱导的急性呼吸窘迫综合征中Nrf2/HO1信号通路来调节巨噬细胞铁死亡。
IL-27 regulates macrophage ferroptosis by inhibiting the Nrf2/HO1 signaling pathway in sepsis-induced ARDS.
作者信息
Xiong Meng, Luo Renjie, Zhang Zhijiao, Liu Panting, Peng Qiaozhi, Xu Fang, Guo Minkang
机构信息
Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, Chongqing, 400016, China.
出版信息
Inflamm Res. 2025 Feb 13;74(1):39. doi: 10.1007/s00011-024-01986-2.
OBJECTIVES
Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulated by macrophages. This study aimed to elucidate the effect of Recombinant Mouse IL-27 Protein on macrophage ferroptosis and polarization, as well as its impact on sepsis-induced ARDS.
METHODS
A cecal ligation and puncture (CLP)-induced sepsis model was established using wild-type (WT) or IL27R mice. Then, the mice were randomly divided into 4 groups: a control group, a CLP group, an IL-27 + CLP combination group, and an IL-27, CLP, and Oltipraz combination group. RAW 264.7 cells and BMDMs were used to further determine the role and mechanism of IL-27 in vitro.
RESULTS
In vitro, IL-27 alone did not alter the expression of proteins linked to the ferroptosis pathway or macrophage polarization. Contrastingly, the combination of IL-27 with LPS further amplified LPS-induced alterations in the ferroptosis pathway, thereby promoting macrophage M1 polarization and inhibiting M2 polarization. Additionally, IL-27 + LPS increased ROS levels in macrophages. A sepsis-induced ARDS mouse model was then established via CLP. In vivo, IL-27 exacerbated CLP-induced lung injury in WT mice. Additionally, it decreased the expression levels of ferroptosis-related proteins (Nrf2, HO-1, GPX4) and increased those of Ptgs2 in the lung tissue of septic mice. Besides, GSH and SOD levels in lung tissue were also reduced. Moreover, IL-27 also promoted M1 polarization and inhibited M2 polarization in macrophages. In IL27R mice, the effects of IL-27 were abrogated. Oltipraz inhibited IL-27-induced changes by up-regulating Nrf2 expression. Overall, this present study demonstrated that the combination of IL-27 and LPS-induced macrophage ferroptosis, promoted macrophage M1 polarization, and inhibited M2 polarization by inhibiting the Nrf2/HO-1 pathway.
CONCLUSION
Oltipraz may alleviate ARDS-related lung injury by up-regulating Nrf2 expression and concurrently inhibiting macrophage ferroptosis.
目的
急性呼吸窘迫综合征（ARDS）是一种发病率和死亡率都很高的临床综合征。脓毒症诱导的ARDS涉及过度的炎症反应，而巨噬细胞可调节这些反应。本研究旨在阐明重组小鼠白细胞介素-27蛋白对巨噬细胞铁死亡和极化的影响，以及其对脓毒症诱导的ARDS的影响。
方法
使用野生型（WT）或IL27R小鼠建立盲肠结扎穿孔（CLP）诱导的脓毒症模型。然后，将小鼠随机分为4组：对照组、CLP组、IL-27 + CLP联合组和IL-27、CLP与奥替普拉联合组。使用RAW 264.7细胞和骨髓来源的巨噬细胞（BMDMs）进一步确定IL-27在体外的作用和机制。
结果
在体外，单独的IL-27不会改变与铁死亡途径或巨噬细胞极化相关的蛋白质表达。相反，IL-27与脂多糖（LPS）的联合进一步放大了LPS诱导的铁死亡途径变化，从而促进巨噬细胞M1极化并抑制M2极化。此外，IL-27 + LPS增加了巨噬细胞中的活性氧（ROS）水平。然后通过CLP建立脓毒症诱导的ARDS小鼠模型。在体内，IL-27加剧了WT小鼠中CLP诱导的肺损伤。此外，它降低了脓毒症小鼠肺组织中铁死亡相关蛋白（Nrf2、HO-1、谷胱甘肽过氧化物酶4（GPX4））的表达水平，并增加了前列腺素内过氧化物合酶2（Ptgs2）的表达水平。此外，肺组织中的谷胱甘肽（GSH）和超氧化物歧化酶（SOD）水平也降低。此外，IL-27还促进了巨噬细胞中的M1极化并抑制了M2极化。在IL27R小鼠中，IL-27的作用被消除。奥替普拉通过上调Nrf2表达抑制了IL-27诱导的变化。总体而言，本研究表明，IL-27与LPS联合诱导巨噬细胞铁死亡，通过抑制Nrf2/HO-1途径促进巨噬细胞M1极化并抑制M2极化。
结论
奥替普拉可能通过上调Nrf2表达并同时抑制巨噬细胞铁死亡来减轻ARDS相关的肺损伤。
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