ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis
Copyright © 2023. Published by Elsevier Inc..
Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:254 |
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| Enthalten in: |
Clinical immunology (Orlando, Fla.) - 254(2023) vom: 05. Sept., Seite 109698 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Tiantian [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.08.2023 Date Revised 22.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.clim.2023.109698 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359812643 |
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| 245 | 1 | 0 | |a ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis |
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| 500 | |a Date Completed 15.08.2023 | ||
| 500 | |a Date Revised 22.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023. Published by Elsevier Inc. | ||
| 520 | |a Strengthened glycolysis is crucial for the macrophage pro-inflammatory response during sepsis. Activating transcription factor 4 (ATF4) plays an important role in regulating glucose and lipid metabolic homeostasis in hepatocytes and adipocytes. However, its immunometabolic role in macrophage during sepsis remains largely unknown. In the present study, we found that the expression of ATF4 in peripheral blood mononuclear cells (PBMCs) was increased and associated with glucose metabolism in septic patients. Atf4 knockdown specifically decreased LPS-induced spleen macrophages and serum pro-inflammatory cytokines levels in mice. Moreover, Atf4 knockdown partially blocked LPS-induced pro-inflammatory cytokines, lactate accumulation and glycolytic capacity in RAW264.7. Mechanically, ATF4 binds to the promoter region of hexokinase II (HK2), and interacts with hypoxia inducible factor-1α (HIF-1α) and stabilizes HIF-1α through ubiquitination modification in response to LPS. Furthermore, ATF4-HIF-1α-HK2-glycolysis axis launches pro-inflammatory response in macrophage depending on the activation of mammalian target of rapamycin (mTOR). Importantly, Atf4 overexpression improves the decreased level of pro-inflammatory cytokines and lactate secretion and HK2 expression in LPS-induced tolerant macrophages. In conclusion, we propose a novel function of ATF4 as a crucial glycolytic activator contributing to pro-inflammatory response and improving immune tolerant in macrophage involved in sepsis. So, ATF4 could be a potential new target for immunotherapy of sepsis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Activating transcription factor 4 | |
| 650 | 4 | |a Glycolysis | |
| 650 | 4 | |a Hexokinase II | |
| 650 | 4 | |a Hypoxia inducible factor-1α | |
| 650 | 4 | |a Pro-inflammatory response | |
| 650 | 4 | |a sepsis | |
| 650 | 7 | |a Activating Transcription Factor 4 |2 NLM | |
| 650 | 7 | |a 145891-90-3 |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
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| 650 | 7 | |a Hypoxia-Inducible Factor 1, alpha Subunit |2 NLM | |
| 650 | 7 | |a Lactic Acid |2 NLM | |
| 650 | 7 | |a 33X04XA5AT |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Atf4 protein, mouse |2 NLM | |
| 700 | 1 | |a Wen, Zhenliang |e verfasserin |4 aut | |
| 700 | 1 | |a Shao, Lujing |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Xiaomeng |e verfasserin |4 aut | |
| 700 | 1 | |a Miao, Huijie |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Jingyi |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Linlin |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Shuyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yilin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Qiming |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Dechang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yucai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chunxia |e verfasserin |4 aut | |
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