IBR1, a novel endogenous IFIH1-binding dsRNA, governs IFIH1 activation and M1 macrophage polarisation in ARDS

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-09-23 DOI:10.1002/ctm2.70027

Shi Zhang, Wei Huang, Xueling Wu, Hanbing Chen, Lu Wang, Jie Chao, Jianfeng Xie, Haibo Qiu

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引用次数: 0

Abstract

Background

Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear.

Methods

In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14⁺ cells obtained from the peripheral blood of 140 ARDS patients.

Results

Our investigation revealed that lipopolysaccharide, a critical component derived from Gram-negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1-binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double-stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double-stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1-induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram-negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury.

Conclusions

This study revealed a novel mechanism involving IBR1, an endogenous double-stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS.

Highlights

In monocytes and macrophages, the endogenous double-stranded RNA, IFIH1-binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double-stranded structure.
IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram-negative bacteria or lipopolysaccharide (LPS).
Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients.

Abstract Image

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IBR1是一种新型内源性IFIH1结合dsRNA，它在ARDS中控制着IFIH1的激活和M1巨噬细胞的极化。

背景：巨噬细胞和单核细胞引起的不受控制的炎症在急性呼吸窘迫综合征（ARDS）恶化中起着至关重要的作用。先前的研究强调了 IFIH1 在调节肺炎引发的 ARDS 中巨噬细胞极化的重要性。然而，IFIH1在ARDS中被激活的机制仍不清楚：在这项研究中，我们利用多组学测序和分子相互作用实验来探索 ARDS 中 IFIH1 激活的分子机制。通过使用条件基因敲除小鼠和原代细胞，我们证明了这些机制在 ARDS 的发生发展中的重要作用。此外，我们还通过对140名ARDS患者外周血中的CD14+细胞进行定量PCR分析，验证了这些机制与ARDS之间的关联：我们的研究发现，脂多糖（一种来自革兰氏阴性细菌的重要成分）通过上调单核细胞和巨噬细胞中一种名为 IFIH1 结合 RNA1（IBR1）的新转录本激活了 IFIH1。具体来说，作为一种内源性双链 RNA，IBR1 因其独特的双链结构而与 IFIH1 的螺旋酶结构域结合。缺失 IBR1 能显著减少 IFIH1 的激活、巨噬细胞的 M1 极化以及 ARDS 中的炎性肺损伤。此外，IBR1 直接诱导巨噬细胞的 M1 极化和 ARDS，而 IFIH1 的缺失则抑制了 IBR1 诱导的巨噬细胞 M1 极化和炎性肺损伤。重要的是，我们观察到，在革兰氏阴性菌引起肺炎的 ARDS 患者中，IBR1 的表达明显增加。此外，我们还证明，通过外泌体递送 IFIH1 突变体可有效抵消 IBR1，从而减轻肺部炎症并缓解肺损伤：这项研究揭示了一种涉及 IBR1 的新机制，IBR1 是一种与 IFIH1 结合的内源性双链 RNA（dsRNA），它揭示了 ARDS 中巨噬细胞极化的复杂过程。服用IFIH1变体有可能消除肺部dsRNA，减轻ARDS的炎性肺损伤：在单核细胞和巨噬细胞中，内源性双链 RNA IFIH1-binding RNA 1（IBR1）因其独特的双链结构而与 IFIH1 的螺旋酶结构域结合。IBR1 在巨噬细胞极化和由革兰氏阴性细菌或脂多糖（LPS）诱发的急性呼吸窘迫综合征（ARDS）的发展过程中发挥着重要作用。服用 IFIH1 变体有可能消除肺 IBR1，减轻 ARDS 患者的肺部炎症损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.