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

Critical Care

卷:25

Xueyin Shi¹  Wei Wang¹  Chengmi Zhang¹  Haiying Ji¹  Xingyu Tong¹  Ran Xia¹  Yang Jiao²  Zhengliang Ma²  Ti Zhang³ 

[1] Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University;

[2] Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School;

[3] National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine;

关键词: Sepsis-related acute lung injury;    Neutrophil;    Macrophage;    Exosomes;    miR-30d-5p;    Pyroptosis;   

DOI  :  10.1186/s13054-021-03775-3

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown