Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved..
BACKGROUND: Massive hepatocyte death is the core event in acute liver failure (ALF). Gasdermin D (GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death. However, the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.
AIM: To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.
METHODS: The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot. GSDMD short hairpin RNA (shRNA) was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1 (MCP1) and its receptor CC chemokine receptor-2 (CCR2) in vitro. For in vivo experiments, we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide (D-Galn/LPS)-induced ALF mouse model.
RESULTS: The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly. The level of GSDMD-N protein increased most obviously (P < 0.001). In vitro, downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins (P < 0.01). In vivo, GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of D-Galn/LPS-induced ALF mice (P < 0.001). Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin (IL)-1β and IL-18, GSDMD-mediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death. However, this pathological process was inhibited after knocking down GSDMD.
CONCLUSION: GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF, recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses. GSDMD knockout can reduce hepatocyte death and inflammatory responses, thus alleviating ALF.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
World journal of gastroenterology - 25(2019), 44 vom: 28. Nov., Seite 6527-6540 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Hong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.05.2020 Date Revised 08.06.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.3748/wjg.v25.i44.6527 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304045349 |
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| 041 | |a eng | ||
| 100 | 1 | |a Li, Hong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 08.05.2020 | ||
| 500 | |a Date Revised 08.06.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Massive hepatocyte death is the core event in acute liver failure (ALF). Gasdermin D (GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death. However, the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear | ||
| 520 | |a AIM: To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments | ||
| 520 | |a METHODS: The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot. GSDMD short hairpin RNA (shRNA) was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1 (MCP1) and its receptor CC chemokine receptor-2 (CCR2) in vitro. For in vivo experiments, we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide (D-Galn/LPS)-induced ALF mouse model | ||
| 520 | |a RESULTS: The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly. The level of GSDMD-N protein increased most obviously (P < 0.001). In vitro, downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins (P < 0.01). In vivo, GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of D-Galn/LPS-induced ALF mice (P < 0.001). Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin (IL)-1β and IL-18, GSDMD-mediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death. However, this pathological process was inhibited after knocking down GSDMD | ||
| 520 | |a CONCLUSION: GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF, recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses. GSDMD knockout can reduce hepatocyte death and inflammatory responses, thus alleviating ALF | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute liver failure | |
| 650 | 4 | |a Gasdermin D | |
| 650 | 4 | |a Hepatocyte | |
| 650 | 4 | |a Monocyte chemotactic protein 1/CC chemokine receptor-2 | |
| 650 | 4 | |a Pyroptosis | |
| 650 | 7 | |a CCL2 protein, human |2 NLM | |
| 650 | 7 | |a CCR2 protein, human |2 NLM | |
| 650 | 7 | |a Ccl2 protein, mouse |2 NLM | |
| 650 | 7 | |a Ccr2 protein, mouse |2 NLM | |
| 650 | 7 | |a Chemokine CCL2 |2 NLM | |
| 650 | 7 | |a GSDMD protein, human |2 NLM | |
| 650 | 7 | |a Gsdmd protein, mouse |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Phosphate-Binding Proteins |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a Receptors, CCR2 |2 NLM | |
| 700 | 1 | |a Zhao, Xue-Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Yi-Ju |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Quan |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Ming-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ya |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Ming-Liang |e verfasserin |4 aut | |
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