Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure
Background and AimsAcute-on-chronic liver failure (ACLF) is characterized by systemic inflammation accompanied by defective anti-bacterial immunity. The role of neutrophils in immune derangement of ACLF has not been fully elucidated. This study is aimed to characterize the role of circulating neutro...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.620365/full |
| _version_ | 1818419899924480000 |
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| author | Wei Wu Shanshan Sun Yijie Wang Ruihong Zhao Haotang Ren Zhiwei Li Hong Zhao Yi Zhang Yi Zhang Jifang Sheng Zhi Chen Yu Shi |
| author_facet | Wei Wu Shanshan Sun Yijie Wang Ruihong Zhao Haotang Ren Zhiwei Li Hong Zhao Yi Zhang Yi Zhang Jifang Sheng Zhi Chen Yu Shi |
| author_sort | Wei Wu |
| collection | DOAJ |
| description | Background and AimsAcute-on-chronic liver failure (ACLF) is characterized by systemic inflammation accompanied by defective anti-bacterial immunity. The role of neutrophils in immune derangement of ACLF has not been fully elucidated. This study is aimed to characterize the role of circulating neutrophils in HBV-related ACLF patients.MethodsQuantitative, phenotypic, transcriptomic, and functional alterations of circulating neutrophils were compared in ACLF and non-ACLF subjects and analyzed for associations with short-term outcomes. Interventional experiments were performed to test the impact on ACLF-patient neutrophil function in vitro.ResultsCirculating absolute neutrophil count was significantly increased in patients with ACLF and was an independent risk factor for 28-day mortality. ACLF-patient neutrophils differentially expressed a panel of surface markers (include TLR-1, TLR-2, TLR-4, CEACAM-1 and FPR1), as well as a distinct transcriptomic signature. ACLF-neutrophils displayed significantly impaired phagocytosis but an increased capacity to form neutrophil extracellular traps (NETs), which was more pronounced in patients with poor outcome. Healthy neutrophils mimicked functional characteristics of ACLF counterpart after co-cultured with plasma from ACLF patients. The oxidative burst and cytokine production capacities remained unchanged. Plasma GM-CSF, IL-6, IL-8, IL-10, and IP-10 levels, as well as lipopolysaccharide (LPS) concentration, were markedly elevated in ACLF patients but not DAMP molecules HMGB-1 and HSP70. Finally, a glycolysis inhibitor, 2-deoxy-glucose, reduced NET formation of ACLF patients’ neutrophils.ConclusionsCirculating ACLF-patient neutrophils exhibit alterations in number, phenotype, gene expression and function, which was associated with poor outcome and shaped by the ACLF circulatory environment. Inhibiting glycolysis can reverse neutrophil dysfunction in ACLF patients. |
| first_indexed | 2024-12-14T12:45:54Z |
| format | Article |
| id | doaj.art-33bea130fa894526a52a8cfd72fb2e61 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T12:45:54Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-33bea130fa894526a52a8cfd72fb2e612022-12-21T23:00:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.620365620365Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver FailureWei Wu0Shanshan Sun1Yijie Wang2Ruihong Zhao3Haotang Ren4Zhiwei Li5Hong Zhao6Yi Zhang7Yi Zhang8Jifang Sheng9Zhi Chen10Yu Shi11State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University Cytometry, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaKey Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaBackground and AimsAcute-on-chronic liver failure (ACLF) is characterized by systemic inflammation accompanied by defective anti-bacterial immunity. The role of neutrophils in immune derangement of ACLF has not been fully elucidated. This study is aimed to characterize the role of circulating neutrophils in HBV-related ACLF patients.MethodsQuantitative, phenotypic, transcriptomic, and functional alterations of circulating neutrophils were compared in ACLF and non-ACLF subjects and analyzed for associations with short-term outcomes. Interventional experiments were performed to test the impact on ACLF-patient neutrophil function in vitro.ResultsCirculating absolute neutrophil count was significantly increased in patients with ACLF and was an independent risk factor for 28-day mortality. ACLF-patient neutrophils differentially expressed a panel of surface markers (include TLR-1, TLR-2, TLR-4, CEACAM-1 and FPR1), as well as a distinct transcriptomic signature. ACLF-neutrophils displayed significantly impaired phagocytosis but an increased capacity to form neutrophil extracellular traps (NETs), which was more pronounced in patients with poor outcome. Healthy neutrophils mimicked functional characteristics of ACLF counterpart after co-cultured with plasma from ACLF patients. The oxidative burst and cytokine production capacities remained unchanged. Plasma GM-CSF, IL-6, IL-8, IL-10, and IP-10 levels, as well as lipopolysaccharide (LPS) concentration, were markedly elevated in ACLF patients but not DAMP molecules HMGB-1 and HSP70. Finally, a glycolysis inhibitor, 2-deoxy-glucose, reduced NET formation of ACLF patients’ neutrophils.ConclusionsCirculating ACLF-patient neutrophils exhibit alterations in number, phenotype, gene expression and function, which was associated with poor outcome and shaped by the ACLF circulatory environment. Inhibiting glycolysis can reverse neutrophil dysfunction in ACLF patients.https://www.frontiersin.org/articles/10.3389/fimmu.2021.620365/fullhepatitis B virusacute-on-chronic liver failureneutrophilphagocytosisNET |
| spellingShingle | Wei Wu Shanshan Sun Yijie Wang Ruihong Zhao Haotang Ren Zhiwei Li Hong Zhao Yi Zhang Yi Zhang Jifang Sheng Zhi Chen Yu Shi Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure Frontiers in Immunology hepatitis B virus acute-on-chronic liver failure neutrophil phagocytosis NET |
| title | Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure |
| title_full | Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure |
| title_fullStr | Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure |
| title_full_unstemmed | Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure |
| title_short | Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure |
| title_sort | circulating neutrophil dysfunction in hbv related acute on chronic liver failure |
| topic | hepatitis B virus acute-on-chronic liver failure neutrophil phagocytosis NET |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.620365/full |
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