Exosomal PGE2 from M2 macrophages inhibits neutrophil recruitment and NET formation through lipid mediator class switching in sepsis

• Published in: Journal of biomedical science 2023-08, Vol.30 (1), p.62-62, Article 62
• Main Authors: Jiao, Yang, Zhang, Ti, Liu, Mei, Zhou, Luyang, Qi, Mengzhi, Xie, Xin, Shi, Xueyin, Gu, Xiaoping, Ma, Zhengliang
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Biosynthesis; Blood & organ donations; Cell culture; Chemokines; China; Class switching; CXCR2 protein; Dinoprostone - metabolism; Dinoprostone - pharmacology; Down-regulation; Ethylenediaminetetraacetic acid; Exosomes; Extracellular Traps; Immunofluorescence; Immunoglobulin Class Switching; Immunohistochemistry; Infection; Inflammation; Inflammatory diseases; Injury prevention; Leukocyte migration; Leukocytes (neutrophilic); Leukocytes (polymorphonuclear); Leukotriene B4; Lipid mediator class switching; Lipids; Lipoxin A4; Lipoxygenase; Lung diseases; Lung Injury - metabolism; Lungs; M2 macrophage-derived exosomes; Macrophages; Mice; Mice, Inbred C57BL; Migration; Morphology; Mortality; Multiple organ dysfunction syndrome; Neutrophil extracellular traps; Neutrophil Infiltration; Neutrophils; Neutrophils - metabolism; Patients; Penicillin; Plasma; Platelet Activating Factor - metabolism; Platelet Activating Factor - pharmacology; Prostaglandin E2; Prostaglandins E; Reactive oxygen species; Receptors; Sepsis; Switching; United Kingdom
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-023-00957-9

Excess polymorphonuclear neutrophil (PMN) recruitment or excessive neutrophil extracellular trap (NET) formation can lead to the development of multiple organ dysfunction during sepsis. M2 macrophage-derived exosomes (M2-Exos) have exhibited anti-inflammatory activities in some inflammatory diseases to mediate organ functional protection, but their role in treating sepsis-related acute lung injury (ALI) remains unclear. In this study, we sought to investigate whether M2-Exos could prevent potentially deleterious inflammatory effects during sepsis-related ALI by modulating abnormal PMN behaviours. C57BL/6 wild-type mice were subjected to a caecal ligation and puncture (CLP) mouse model to mimic sepsis in vivo, and M2-Exos were administered intraperitoneally 1 h after CLP. H&E staining, immunofluorescence and immunohistochemistry were conducted to investigate lung tissue injury, PMN infiltration and NET formation in the lung. We further demonstrated the role of M2-Exos on PMN function and explored the potential mechanisms through an in vitro coculture experiment using PMNs isolated from both healthy volunteers and septic patients. Here, we report that M2-Exos inhibited PMN migration and NET formation, alleviated lung injury and reduced mortality in a sepsis mouse model. In vitro, M2-Exos significantly decreased PMN migration and NET formation capacity, leading to lipid mediator class switching from proinflammatory leukotriene B4 (LTB4) to anti-inflammatory lipoxin A4 (LXA4) by upregulating 15-lipoxygenase (15-LO) expression in PMNs. Treatment with LXA4 receptor antagonist attenuated the effect of M2-Exos on PMNs and lung injury. Mechanistically, prostaglandin E2 (PGE2) enriched in M2-Exos was necessary to increase 15-LO expression in PMNs by functioning on the EP4 receptor, upregulate LXA4 production to downregulate chemokine (C-X-C motif) receptor 2 (CXCR2) and reactive oxygen species (ROS) expressions, and finally inhibit PMN function. Our findings reveal a previously unknown role of M2-Exos in regulating PMN migration and NET formation through lipid mediator class switching, thus highlighting the potential application of M2-Exos in controlling PMN-mediated tissue injury in patients with sepsis.