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Human CRP protects against acetaminophen-induced liver injury in mice

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Could CRP replace N-acetylcysteine?

Acetaminophen is one of the most widely used pain relievers in the world. Acetaminophen use is considered safe at therapeutic doses; however it is a dose-dependent hepatotoxin, and acetaminophen overdose is one of the leading causes of acute liver failure (ALF) in industrialized countries. Despite intensive efforts, the mechanisms involved in acetaminophen hepatotoxicity are not fully understood, which has hampered the availability of effective therapy for acetaminophen hepatotoxicity.

In Cellular and Molecular Gastroenterology and Hepatology, Li et al. uncovered a crucial role of C-reactive protein in acetaminophen-mediated ALF. Despite its well recognized role as an acute-phase protein in inflammation, CRP also regulates complement activation and hence the modulation of immune cell responses and the generation of anaphylotoxins via specific receptors. With use of models of genetic deletion of CRP in rats and mice, Li et al. demonstrate a protective role for CRP in acetaminophen-induced ALF by regulating the late phase of acetaminophen-induced liver failure via complement overactivation through antagonism of C3aR that prevented neutrophil recruitment.

From a clinically relevant perspective, the protective effect of CRP was more effective than the currently used therapeutic approach of giving N-acetylcysteine (NAC) to patients after acetaminophen hepatotoxicity. The superiority of CRP vs. NAC is related to the limited period for NAC administration after acetaminophen overdose, while the administration of CRP was effective even when given several hours after acetaminophen dosage, consistent with its ability to target the late phase of events involved in acetaminophen hepatotoxicity. Therefore, these findings identify CRP as a promising approach for acetaminophen hepatotoxicity with significant therapeutic advantage, compared with NAC treatment, which may change the paradigm of management of acetaminophen-induced liver failure.

Jose C. Fernandez-Checa, PhD, is a professor at the Spanish National Research Council at the Institute of Biomedical Research of Barcelona, investigator of the Institute of Biomedical Research August Pi i Sunyer, group leader of the Center for Biomedical Network Research on Hepatic and Digestive Diseases, and visiting professor at the department of medicine University of Southern California, Los Angeles. He has no relevant conflicts of interest.



While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

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