C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary

Background and aims: C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI). Methods: The effects of CRP in AILI were investigated using CRP knockout mice a...

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Autores principales:	Hai-Yun Li, Zhao-Ming Tang, Zhe Wang, Jian-Min Lv, Xiao-Ling Liu, Yu-Lin Liang, Bin Cheng, Ning Gao, Shang-Rong Ji, Yi Wu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Biomarker Hepatocytes Inflammation Pattern Recognition Receptor Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/4afa67898b254ba4beeb3bfd2a78aa05
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spelling	oai:doaj.org-article:4afa67898b254ba4beeb3bfd2a78aa052021-11-14T04:34:18ZC-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary2352-345X10.1016/j.jcmgh.2021.09.003https://doaj.org/article/4afa67898b254ba4beeb3bfd2a78aa052022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001910https://doaj.org/toc/2352-345XBackground and aims: C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI). Methods: The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in vitro and in mice with Fcγ receptor 2B knockout, C3 knockout, or hepatic expression of CRP mutants defective in complement interaction. The therapeutic potential of CRP was investigated by intraperitoneal administration at 2 or 6 hours post–AILI induction in wild-type mice. Results: CRP knockout exacerbated AILI in mice and rats, which could be rescued by genetic knock-in, adeno-associated virus–mediated hepatic expression or direct administration of human CRP. Mechanistically, CRP does not act via its cellular receptor Fcγ receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on already injured hepatocytes, thereby suppressing the late phase amplification of inflammation likely mediated by C3a-dependent actions of neutrophils. Importantly, CRP treatment effectively alleviated AILI with a significantly extended therapeutic time window than that of N-acetyl cysteine. Conclusion: Our results thus identify CRP as a crucial checkpoint that limits destructive activation of complement in acute liver injury, and we argue that long-term suppression of CRP expression or function might increase the susceptibility to AILI.Hai-Yun LiZhao-Ming TangZhe WangJian-Min LvXiao-Ling LiuYu-Lin LiangBin ChengNing GaoShang-Rong JiYi WuElsevierarticleBiomarkerHepatocytesInflammationPattern Recognition ReceptorDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 289-307 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biomarker Hepatocytes Inflammation Pattern Recognition Receptor Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Biomarker Hepatocytes Inflammation Pattern Recognition Receptor Diseases of the digestive system. Gastroenterology RC799-869 Hai-Yun Li Zhao-Ming Tang Zhe Wang Jian-Min Lv Xiao-Ling Liu Yu-Lin Liang Bin Cheng Ning Gao Shang-Rong Ji Yi Wu C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary
description	Background and aims: C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI). Methods: The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in vitro and in mice with Fcγ receptor 2B knockout, C3 knockout, or hepatic expression of CRP mutants defective in complement interaction. The therapeutic potential of CRP was investigated by intraperitoneal administration at 2 or 6 hours post–AILI induction in wild-type mice. Results: CRP knockout exacerbated AILI in mice and rats, which could be rescued by genetic knock-in, adeno-associated virus–mediated hepatic expression or direct administration of human CRP. Mechanistically, CRP does not act via its cellular receptor Fcγ receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on already injured hepatocytes, thereby suppressing the late phase amplification of inflammation likely mediated by C3a-dependent actions of neutrophils. Importantly, CRP treatment effectively alleviated AILI with a significantly extended therapeutic time window than that of N-acetyl cysteine. Conclusion: Our results thus identify CRP as a crucial checkpoint that limits destructive activation of complement in acute liver injury, and we argue that long-term suppression of CRP expression or function might increase the susceptibility to AILI.
format	article
author	Hai-Yun Li Zhao-Ming Tang Zhe Wang Jian-Min Lv Xiao-Ling Liu Yu-Lin Liang Bin Cheng Ning Gao Shang-Rong Ji Yi Wu
author_facet	Hai-Yun Li Zhao-Ming Tang Zhe Wang Jian-Min Lv Xiao-Ling Liu Yu-Lin Liang Bin Cheng Ning Gao Shang-Rong Ji Yi Wu
author_sort	Hai-Yun Li
title	C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary
title_short	C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary
title_full	C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary
title_fullStr	C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary
title_full_unstemmed	C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary
title_sort	c-reactive protein protects against acetaminophen-induced liver injury by preventing complement overactivationsummary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/4afa67898b254ba4beeb3bfd2a78aa05
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C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement OveractivationSummary

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