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

Abstract

C-reactive protein is a critical checkpoint that limits destructive activation of complement in acetaminopheninduced liver injury, and could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose.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 Fcg 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 Fcg receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on 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.

C-Reactive Protein, a Promising Approach for Acetaminophen Hepatotoxicity

“…Moreover, coadministration of NAC improved the therapeutic efficacy of CRP at 2 hours, but showed no improvement at 6 hours post APAP administration. Thus, the findings of Li et al 7 further confirm the role of complement overactivation in APAP hepatotoxicity and identify CRP as a promising approach for APAP hepatotoxicity with significant therapeutic advantage compared with NAC treatment, which needs to be further validated in future clinical trials.…”

“…Selective inhibitors against cellular receptors for anaphylatoxins indicated that C3aR but not C5aR antagonist protected against APAP-induced liver injury, lending support for a key role for C3a, but not C5a or membrane attack complex in amplifying the late-phase injury of APAP hepatotoxicity. 7 Interestingly, further studies using CXCR1/2 and CCR2/CCR5 inhibitors identified neutrophils as the cell type that responded to C3a activation, pointing to a potential role for a C3a-neutrophil axis in APAP hepatotoxicity. Unfortunately, this intriguing aspect was not further pursued and will require extensive additional work given the controversial role of neutrophils in APAP hepatotoxicity, and their emerging contribution to host defense and injury resolution following APAP overdose.…”

“…The link between CRP and complement activation in APAP hepatotoxicity has remained elusive so far. In a recent study, Li et al 7 report the protective effect of CRP in APAP hepatotoxicity by preventing the overactivation of complement. In an elegant series of studies using mice and rats in which CRP was deleted, they provide evidence for the protective role of CRP against APAP-induced liver damage.…”

“…These findings therefore highlight that the protective effect of CRP against APAP hepatotoxicity is species independent. Although, as mentioned, CRP can modulate immune cell responses via its cellular receptor FcγR2B to inhibit the early phase injury to hepatocytes induced by APAP, Li et al 7 excluded this mode of action in the protective effects of CRP against APAP hepatotoxicity. Indeed, key players involved in this initial phase of APAP-mediated hepatocellular injury, such as GSH depletion or JNK activation, 8 , 9 were unaffected by CRP rescue, an outcome that could be explained by the lack of expression of FcγR on hepatocytes and validated with the knockout of FcγR2B, an inhibitory FcγR that mediates the anti-inflammatory activities of CRP in mice, because FcγR2B knockout mice exhibited marginal protection against APAP hepatotoxicity.…”

3′mRNA sequencing reveals pro-regenerative properties of c5ar1 during resolution of murine acetaminophen-induced liver injury

“…Notably, C5aR2 activation has been shown to promote release of HMGB1 63 which is evidently pathogenic in APAP-induced ALI 8 . It is furthermore noteworthy that lack of C3 biological function was associated with amelioration of APAP-induced ALI 47 , 64 . Yet, this observation is likely unrelated to C5a receptor functions.…”