Macrophage-derived exosomal miR-2137 regulates pyroptosis in LPS-induced acute lung injury.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-11-16 DOI:10.1016/j.intimp.2024.113549

Cong Ye, Xiaodong Yang, Lin Zhu, Guilin Chang, Yu Hu, Weixi Wang

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引用次数: 0

Abstract

Background: Alveolar macrophages (AMs) play a predominant role in acute lung injury (ALI). However, the role of macrophage-derived exosomal miRNAs in lipopolysaccharide (LPS)-induced ALI has not been determined.

Methods: We previously reported that exosomes in the bronchoalveolar lavage fluid (BALF) of mice with ALI were derived predominantly from macrophages. Exosomal small RNA sequencing was conducted to identify the miRNA profiles. Exosomes derived from LPS-induced macrophages (LPS-exos) were intravenously administered to C57BL/6J mice, after which lung injury and pyroptosis were assessed. LPS-exos were cultured with alveolar epithelial cells (AECs) to further validate the results of the animal studies.

Results: LPS-exos promoted lung inflammation and pyroptosis in vivo and in vitro. MiR-2137 was significantly upregulated in both LPS-exos and in MLE-12 cells. LPS-exos reduced cell viability, promoted the expression of LDH and inflammatory cytokines, and exacerbated vacuolization in MLE-12 cells. The administration of miR-2137 mimics and LPS-treated exosomes further strengthened these effects and enhanced pyroptosis mediated by NLRP3, Caspase1, ASC, and GSDMD. MiR-2137 mediated the effects of LPS-exos by targeting Wnt9a in AECs. In addition, the miR-2137 inhibitor markedly decreased the severity of LPS-exo-induced histological lesions, inflammation and pyroptosis in the lung.

Conclusion: Exosomal miR-2137 derived from AMs contributes to LPS-induced ALI by inducing AEC pyroptosis through the targeting of Wnt9a to activate the Wnt signaling pathway. This study revealed that AMs and AECs interact in ALI, providing novel strategies for ALI treatment.

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巨噬细胞源性外泌体 miR-2137 在 LPS 诱导的急性肺损伤中调控脓毒症。

背景：肺泡巨噬细胞（AMs）在急性肺损伤（ALI）中起主要作用。然而，巨噬细胞衍生的外泌体 miRNA 在脂多糖（LPS）诱导的 ALI 中的作用尚未确定：我们以前曾报道过，ALI 小鼠支气管肺泡灌洗液（BALF）中的外泌体主要来自巨噬细胞。我们进行了外泌体小 RNA 测序，以确定 miRNA 图谱。给 C57BL/6J 小鼠静脉注射从 LPS 诱导的巨噬细胞（LPS-exos）中提取的外泌体，然后评估肺损伤和脓毒症。将 LPS-exos 与肺泡上皮细胞（AECs）一起培养，以进一步验证动物实验的结果：结果：LPS-exos促进了体内和体外的肺部炎症和脓毒症。MiR-2137在LPS-exos和MLE-12细胞中均明显上调。LPS-exos 降低了细胞活力，促进了 LDH 和炎性细胞因子的表达，并加剧了 MLE-12 细胞的空泡化。给MiR-2137模拟物和LPS处理过的外泌体进一步加强了这些效应，并增强了由NLRP3、Caspase1、ASC和GSDMD介导的裂解。MiR-2137 通过靶向 AECs 中的 Wnt9a 来介导 LPS 外泌体的效应。此外，miR-2137抑制剂明显降低了LPS-exos诱导的肺组织学病变、炎症和脓毒症的严重程度：结论：来自AMs的外泌体miR-2137通过靶向Wnt9a激活Wnt信号通路，诱导AEC脓毒症，从而导致LPS诱导的ALI。这项研究揭示了AMs和AECs在ALI中的相互作用，为ALI的治疗提供了新的策略。

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

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.