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
  • 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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