C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement Overactivation.
C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement Overactivation.
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C 反应蛋白通过防止补体过度激活来防止对乙酰氨基酚引起的肝损伤。
DOI：
10.1016/j.jcmgh.2021.09.003
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发表时间：
2022
影响因子：
7.2
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Li HY;Tang ZM;Wang Z;Lv JM;Liu XL;Liang YL;Cheng B;Gao N;Ji SR;Wu Y
C - 反应蛋白（CRP）是一种由肝细胞产生的炎症标志物，但在肝损伤中的功能尚不明确。我们旨在研究CRP在对乙酰氨基酚诱导的肝损伤（AILI）中的作用。
通过使用CRP基因敲除小鼠和大鼠并结合人CRP补救实验，研究了CRP在AILI中的作用。在体外以及Fcγ受体2B基因敲除、C3基因敲除小鼠或肝脏表达补体相互作用缺陷的CRP突变体的小鼠中研究了CRP作用的机制。通过在AILI诱导后2小时或6小时对野生型小鼠进行腹腔注射，研究了CRP的治疗潜力。
CRP基因敲除加剧了小鼠和大鼠的AILI，这可通过基因敲入、腺相关病毒介导的肝脏表达或直接给予人CRP来挽救。从机制上讲，CRP并非通过其细胞受体Fcγ受体2B来抑制对乙酰氨基酚诱导的肝细胞早期损伤；相反，CRP通过因子H抑制补体在已受损肝细胞上的过度激活，从而抑制可能由中性粒细胞的C3a依赖性作用介导的炎症后期放大。重要的是，CRP治疗有效缓解了AILI，且治疗时间窗比N - 乙酰半胱氨酸显著延长。
因此，我们的研究结果确定CRP是限制急性肝损伤中补体破坏性激活的关键检查点，并且我们认为长期抑制CRP的表达或功能可能会增加对AILI的易感性。
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). 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. 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. 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.
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单体 C 反应蛋白结合并中和 NF-κB 配体诱导的破骨细胞分化的受体激活剂
影响因子：
7.3
作者：
Jia ZK;Li HY;Liang YL;Potempa LA;Ji SR;Wu Y
通讯作者：
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影响因子：
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作者：
Braig D;Nero TL;Koch HG;Kaiser B;Wang X;Thiele JR;Morton CJ;Zeller J;Kiefer J;Potempa LA;Mellett NA;Miles LA;Du XJ;Meikle PJ;Huber-Lang M;Stark GB;Parker MW;Peter K;Eisenhardt SU
通讯作者：
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影响因子：
4.8
作者：
Ji, Shang-Rong;Wu, Yi;Zhao, Jing
通讯作者：
Zhao, Jing
DOI：
10.1155/2013/379040
发表时间：
2013-09-14
期刊：
ISRN inflammation
影响因子：
--
作者：
Du Clos TW
通讯作者：
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DOI：
10.1084/jem.192.9.1353
发表时间：
2000-11-06
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Gershov D;Kim S;Brot N;Elkon KB
通讯作者：
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