耐甲氧西林金黄色葡萄球菌（MRSA）感染是医院和社区获得性肺炎的主要原因，死亡率仍然很高。细胞外囊泡（EV）作为细胞间通讯的重要介质，对传染病具有重大影响。然而，来自肺泡巨噬细胞 (AM) 的 EV 在 MRSA 肺炎中的作用仍不清楚。我们报告说，在患有 MRSA 肺炎的小鼠中，AM 会吞噬 MRSA 并释放更多的 EV。来自含有吞噬 MRSA 的 AM 的 EV 表现出显着的促炎作用，并通过传递肿瘤坏死因子 α (TNF-α) 和 miR-146a-5p 诱导坏死性凋亡。从机制上讲，这些 EV 中上调的 miR-146a-5p 通过靶向 TNF 受体相关因子 6 (TRAF6) 增强 RIPK1、RIPK3 和 MLKL 的磷酸化，从而促进 TNF-α 诱导的坏死性凋亡。 TNF-α 拮抗剂和 miR-146a-5p antagomir 的组合可有效改善 MRSA 肺炎小鼠的预后。总体而言，我们揭示了感染 MRSA 的 AM 产生的 EV 的原坏死效应，并为预防和治疗 MRSA 肺炎提供了一个有前景的靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Methicillin-resistant Staphylococcus aureus (MRSA) infection, a major cause of hospital- and community-acquired pneumonia, still has a high mortality rate. Extracellular vesicles (EVs), as crucial mediators of intercellular communication, have a significant impact on infectious diseases. However, the role of EVs from alveolar macrophages (AMs) in MRSA pneumonia remains unclear. We report that AMs phagocytose MRSA and release more EVs in mice with MRSA pneumonia. EVs from AMs harboring phagocytosed MRSA exhibit significant proinflammatory effects and induce necroptosis by delivering tumor necrosis factor α (TNF-α) and miR-146a-5p. Mechanically, the upregulated miR-146a-5p in these EVs enhances the phosphorylation of RIPK1, RIPK3, and MLKL by targeting TNF receptor-associated factor 6 (TRAF6), thereby promoting TNF-α-induced necroptosis. The combination of a TNF-α antagonist and an miR-146a-5p antagomir effectively improves the outcomes of mice with MRSA pneumonia. Overall, we reveal the pronecrotic effect of EVs from MRSA-infected AMs and provide a promising target for the prevention and treatment of MRSA pneumonia.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.