Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Xuehuan Wen
Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Bingyu Li
Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Ruomeng Hu
Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Jie Yang
Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Qing Yu
Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Xianchang Zeng
Institute of Immunology, and Department of Orthopedics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
Huajun Feng
Ecological-Environment & Health College (EEHC), Zhejiang A&F University, Hangzhou, Zhejiang 311300, China; Corresponding author
Feng Zhu
Department of Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China; Corresponding author
Zhijian Cai
Institute of Immunology, and Department of Orthopedics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Corresponding author
Gensheng Zhang
Department of Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang 310009, China; Corresponding author
Summary: 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.
