PMID- 34641966 OWN - NLM STAT- MEDLINE DCOM- 20211222 LR - 20211222 IS - 1466-609X (Electronic) IS - 1364-8535 (Print) IS - 1364-8535 (Linking) VI - 25 IP - 1 DP - 2021 Oct 12 TI - Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. PG - 356 LID - 10.1186/s13054-021-03775-3 [doi] LID - 356 AB - BACKGROUND: Polymorphonuclear neutrophils (PMNs) play an important role in sepsis-related acute lung injury (ALI). Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis-related ALI and the underlying mechanisms remains unclear. METHODS: Tumor necrosis factor-alpha (TNF-alpha), a key regulator of innate immunity in sepsis-related ALI, was used to stimulate PMNs from healthy C57BL/6J mice in vitro. Exosomes isolated from the supernatant were injected to C57BL/6J wild-type mice intraperitoneally (i.p.) and then examined for lung inflammation, macrophage (Mvarphi) polarization and pyroptosis. In vitro co-culture system was applied where the mouse Raw264.7 macrophages or bone marrow-derived macrophages (BMDMs) were co-cultured with PMN-derived exosomes to further confirm the results of in vivo animal study and explore the potential mechanisms involved. RESULTS: Exosomes released by TNF-alpha-stimulated PMNs (TNF-Exo) promoted M1 macrophage activation after in vivo i.p. injection or in vitro co-culture. In addition, TNF-Exo primed macrophage for pyroptosis by upregulating NOD-like receptor 3 (NLRP3) inflammasome expression through nuclear factor kappaB (NF-kappaB) signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting suppressor of cytokine signaling (SOCS-1) and sirtuin 1 (SIRT1) in macrophages. Furthermore, intravenous administration of miR-30d-5p inhibitors significantly decreased TNF-Exo or cecal ligation and puncture (CLP)-induced M1 macrophage activation and macrophage death in the lung, as well as the histological lesions. CONCLUSIONS: The present study demonstrated that exosomal miR-30d-5p from PMNs contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF-kappaB signaling. These findings suggest a novel mechanism of PMN-Mvarphi interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients. CI - (c) 2021. The Author(s). FAU - Jiao, Yang AU - Jiao Y AD - Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China. AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. FAU - Zhang, Ti AU - Zhang T AD - National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. FAU - Zhang, Chengmi AU - Zhang C AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. FAU - Ji, Haiying AU - Ji H AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. FAU - Tong, Xingyu AU - Tong X AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. FAU - Xia, Ran AU - Xia R AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. FAU - Wang, Wei AU - Wang W AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. FAU - Ma, Zhengliang AU - Ma Z AD - Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China. mazhengliang1964@nju.edu.cn. FAU - Shi, Xueyin AU - Shi X AUID- ORCID: 0000-0002-1070-1017 AD - Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. shixueyin1128@163.com. LA - eng GR - 81974292/national natural science foundation of china/ GR - 18411951200/key program of shanghai committee of science and technology/ GR - 82102257/National Natural Science Foundation of China/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211012 PL - England TA - Crit Care JT - Critical care (London, England) JID - 9801902 RN - 0 (MicroRNAs) RN - 0 (NF-kappa B) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - *Acute Lung Injury/etiology MH - Animals MH - Humans MH - Macrophage Activation MH - Macrophages MH - Mice MH - Mice, Inbred C57BL MH - *MicroRNAs MH - NF-kappa B MH - Neutrophils MH - Pyroptosis MH - *Sepsis/complications MH - Tumor Necrosis Factor-alpha PMC - PMC8507252 OTO - NOTNLM OT - Exosomes OT - Macrophage OT - Neutrophil OT - Pyroptosis OT - Sepsis-related acute lung injury OT - miR-30d-5p COIS- The authors declare that they have no competing interests. EDAT- 2021/10/14 06:00 MHDA- 2021/12/24 06:00 PMCR- 2021/10/12 CRDT- 2021/10/13 05:44 PHST- 2021/06/27 00:00 [received] PHST- 2021/09/27 00:00 [accepted] PHST- 2021/10/13 05:44 [entrez] PHST- 2021/10/14 06:00 [pubmed] PHST- 2021/12/24 06:00 [medline] PHST- 2021/10/12 00:00 [pmc-release] AID - 10.1186/s13054-021-03775-3 [pii] AID - 3775 [pii] AID - 10.1186/s13054-021-03775-3 [doi] PST - epublish SO - Crit Care. 2021 Oct 12;25(1):356. doi: 10.1186/s13054-021-03775-3.