2. Academic Validation
  3. Exosomal PGE2 from M2 macrophages inhibits neutrophil recruitment and NET formation through lipid mediator class switching in sepsis

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

  • J Biomed Sci. 2023 Aug 2;30(1):62. doi: 10.1186/s12929-023-00957-9.
Yang Jiao # 1,  Ti Zhang # 2,  Mei Liu # 1,  Luyang Zhou 1,  Mengzhi Qi 3,  Xin Xie 1,  Xueyin Shi 4,  Xiaoping Gu 5,  Zhengliang Ma 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
  • 2 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
  • 3 Department of Intensive Care Unit, Nanjing Drum Tower Hospital, The Affliated Hospital of Nanjing University Medical School, Nanjing, China.
  • 4 Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. [email protected].
  • 5 Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China. [email protected].
  • 6 Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China. [email protected].
  • # Contributed equally.
PMID: 37533081 DOI: 10.1186/s12929-023-00957-9
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Lipid mediator class switching; M2 macrophage-derived exosomes; Migration; Neutrophil extracellular traps; Neutrophils.

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