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Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

BACKGROUND: Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immuno...

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Autores principales: Pan, Tingting, Sun, Shaoqiong, Chen, Yang, Tian, Rui, Chen, Erzhen, Tan, Ruoming, Wang, Xiaoli, Liu, Zhaojun, Liu, Jialin, Qu, Hongping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796568/
https://www.ncbi.nlm.nih.gov/pubmed/35090526
http://dx.doi.org/10.1186/s13054-022-03893-6
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author Pan, Tingting
Sun, Shaoqiong
Chen, Yang
Tian, Rui
Chen, Erzhen
Tan, Ruoming
Wang, Xiaoli
Liu, Zhaojun
Liu, Jialin
Qu, Hongping
author_facet Pan, Tingting
Sun, Shaoqiong
Chen, Yang
Tian, Rui
Chen, Erzhen
Tan, Ruoming
Wang, Xiaoli
Liu, Zhaojun
Liu, Jialin
Qu, Hongping
author_sort Pan, Tingting
collection PubMed
description BACKGROUND: Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis. METHODS: Metabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated. RESULTS: Transcriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs’ chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs’ chemotaxis and phagocytosis functions. CONCLUSIONS: The inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-022-03893-6.
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spelling pubmed-87965682022-02-02 Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis Pan, Tingting Sun, Shaoqiong Chen, Yang Tian, Rui Chen, Erzhen Tan, Ruoming Wang, Xiaoli Liu, Zhaojun Liu, Jialin Qu, Hongping Crit Care Research BACKGROUND: Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis. METHODS: Metabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated. RESULTS: Transcriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs’ chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs’ chemotaxis and phagocytosis functions. CONCLUSIONS: The inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13054-022-03893-6. BioMed Central 2022-01-28 /pmc/articles/PMC8796568/ /pubmed/35090526 http://dx.doi.org/10.1186/s13054-022-03893-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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.
spellingShingle Research
Pan, Tingting
Sun, Shaoqiong
Chen, Yang
Tian, Rui
Chen, Erzhen
Tan, Ruoming
Wang, Xiaoli
Liu, Zhaojun
Liu, Jialin
Qu, Hongping
Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
title Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
title_full Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
title_fullStr Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
title_full_unstemmed Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
title_short Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
title_sort immune effects of pi3k/akt/hif-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796568/
https://www.ncbi.nlm.nih.gov/pubmed/35090526
http://dx.doi.org/10.1186/s13054-022-03893-6
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