Abstract：
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.
摘要：
耐甲氧西林金黄色葡萄球菌(MRSA)感染,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），作为细胞间通讯的关键媒介，对传染病有重大影响。然而,来自肺泡巨噬细胞(AMs)的EVs在MRSA肺炎中的作用尚不清楚.我们报告说，AMs吞噬MRSA并在MRSA肺炎小鼠中释放更多的EV。来自具有吞噬MRSA的AMs的EV表现出明显的促炎作用，并通过递送肿瘤坏死因子α（TNF-α）和miR-146a-5p诱导坏死。机械上,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。TNF-α拮抗剂和miR-146a-5pantagomir的组合可有效改善MRSA肺炎小鼠的预后。总的来说,我们揭示了由MRSA感染的AMs产生的EVs的外阴效应,并为MRSA肺炎的预防和治疗提供了一个有希望的靶点.
