Article

Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury

Yang JiaoDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, ChinaTi ZhangNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, ChinaChengmi ZhangDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, ChinaHaiying JiDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, ChinaXingyu TongDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, ChinaXia RanDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, ChinaWei WangDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, ChinaZhengliang MaDepartment of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China. [email protected]Xueyin ShiDepartment of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. [email protected]

2021en

ABI

Abstract

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-α (TNF-α), 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 (Mϕ) 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-α-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 κB (NF-κB) 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-κB signaling. These findings suggest a novel mechanism of PMN-Mϕ interaction in sepsis-related ALI, which may provide new therapeutic strategies in sepsis patients.

Identifiers

DOI: 10.1186/s13054-021-03775-3

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