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

Cell Mol Gastroenterol Hepatol. 2022;13(1):289-307. doi: 10.1016/j.jcmgh.2021.09.003. Epub 2021 Sep 16.


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.

Keywords: Biomarker; Hepatocytes; Inflammation; Pattern Recognition Receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / adverse effects
  • Animals
  • C-Reactive Protein
  • Chemical and Drug Induced Liver Injury*
  • Chemical and Drug Induced Liver Injury, Chronic*
  • Mice
  • Mice, Inbred C57BL
  • Rats


  • Acetaminophen
  • C-Reactive Protein