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

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          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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12929-023-00957-9.

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          Most cited references53

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.

            Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.
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              Lipid mediators in the resolution of inflammation.

              Mounting of the acute inflammatory response is crucial for host defense and pivotal to the development of chronic inflammation, fibrosis, or abscess formation versus the protective response and the need of the host tissues to return to homeostasis. Within self-limited acute inflammatory exudates, novel families of lipid mediators are identified, named resolvins (Rv), protectins, and maresins, which actively stimulate cardinal signs of resolution, namely, cessation of leukocytic infiltration, counterregulation of proinflammatory mediators, and the uptake of apoptotic neutrophils and cellular debris. The biosynthesis of these resolution-phase mediators in sensu stricto is initiated during lipid-mediator class switching, in which the classic initiators of acute inflammation, prostaglandins and leukotrienes (LTs), switch to produce specialized proresolving mediators (SPMs). In this work, we review recent evidence on the structure and functional roles of these novel lipid mediators of resolution. Together, these show that leukocyte trafficking and temporal spatial signals govern the resolution of self-limited inflammation and stimulate homeostasis.
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                Author and article information

                Contributors
                shixueyin1128@163.com
                xiaopinggu@whu.edu.cn
                mazhengliang1964@nju.edu.cn
                Journal
                J Biomed Sci
                J Biomed Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                2 August 2023
                2 August 2023
                2023
                : 30
                : 62
                Affiliations
                [1 ]GRID grid.428392.6, ISNI 0000 0004 1800 1685, Department of Anesthesiology, Nanjing Drum Tower Hospital, , The Affliated Hospital of Nanjing University Medical School, ; 321 Zhongshan Road, Nanjing, 210008 China
                [2 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Anesthesiology and Intensive Care Unit, Xinhua Hospital, School of Medicine, , Shanghai Jiaotong University, ; 1665 Kongjiang Road, Shanghai, 200092 China
                [3 ]GRID grid.41156.37, ISNI 0000 0001 2314 964X, National Clinical Research Center of Kidney Diseases, Jinling Hospital, , Nanjing University School of Medicine, ; Nanjing, China
                [4 ]GRID grid.428392.6, ISNI 0000 0004 1800 1685, Department of Intensive Care Unit, Nanjing Drum Tower Hospital, , The Affliated Hospital of Nanjing University Medical School, ; Nanjing, China
                Author information
                http://orcid.org/0000-0001-6524-4186
                Article
                957
                10.1186/s12929-023-00957-9
                10394797
                37533081
                348db189-7899-4b8c-bc9c-80b300607312
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 19 April 2023
                : 24 July 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82171225
                Award ID: 81971044
                Award ID: 82102257
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100017594, Medical Science and Technology Project of Zhejiang Province;
                Award ID: ZKX22014
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100010031, Postdoctoral Research Foundation of China;
                Award ID: 2022M711583
                Award Recipient :
                Categories
                Research
                Custom metadata
                © National Science Council of the Republic of China (Taiwan) 2023

                Molecular medicine
                m2 macrophage-derived exosomes,neutrophils,migration,neutrophil extracellular traps,lipid mediator class switching

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