Abstract
Toll-like receptor (TLR) activation has been implicated in acetaminophen (APAP)-induced hepatotoxicity. Herein, we hypothesize that TLR3 activation significantly contributed to APAP-induced liver injury. In fasted wildtype (WT) mice, APAP caused significant cellular necrosis, edema, and inflammation in the liver, and the de novo expression and activation of TLR3 was found to be necessary for APAP-induced liver failure. Specifically, liver tissues from similarly fasted TLR3-deficient (tlr3−/−) mice exhibited significantly less histological and biochemical evidence of injury after APAP challenge. Similar protective effects were observed in WT mice in which TLR3 was targeted through immunoneutralization at 3 h post-APAP challenge. Among three important death ligands (i.e. TNFα, TRAIL, and FASL) known to promote hepatocyte death after APAP challenge, TNFα was the only ligand that was significantly reduced in APAP-challenged tlr3−/− mice compared with APAP-challenged WT controls. In vivo studies demonstrated that TLR3 activation contributed to TNFα production in the liver presumably via F4/80+ and CD11c+ immune cells. In vitro studies indicated that there was cooperation between TNFα and TLR3 in the activation of JNK signaling in isolated and cultured liver epithelial cells (i.e. nMuLi). Moreover, TLR3 activation enhanced the expression of phosphorylated JNK in APAP injured livers. Thus, the current study demonstrates that TLR3 activation contributes to APAP-induced hepatotoxicity.
Highlights
Acetaminophen (N-acetyl-para-aminophenol (APAP)) overdose remains one of the most common reasons for drug-induced liver injury in the United States and the United Kingdom, accounting for approximately one third of the cases of acute liver failure [1]
It was apparent that TLR3 was expressed in hepatocytes and in other cells localized in the liver during activation has been implicated in acetaminophen (APAP) injury (Figure 1B)
TLR3 expression in primary hepatocytes was not affected by APAP challenge alone, the addition of TNFa+a TLR3 ligand (PolyI:C) or PolyI:C alone significantly increased the expression of this receptor (Figure 1D)
Summary
Acetaminophen (N-acetyl-para-aminophenol (APAP)) overdose remains one of the most common reasons for drug-induced liver injury in the United States and the United Kingdom, accounting for approximately one third of the cases of acute liver failure [1]. APAP-induced hepatotoxicity is the consequence of the generation of toxic metabolites from APAP, which lead to hepatocyte death by necrosis and apoptosis. Hepatocyte death leads to secondary activation of the innate immune response involving upregulation of inflammatory cytokines and chemokines and the infiltration of various inflammatory cell types [4,5,6]. The mechanism(s) leading to the initial hepatocyte injury and subsequent inflammatory response during APAP-induced acute liver failure has generated considerable research interest since a more complete understanding of this process might lead to viable therapeutic options following APAP overdose. Because TLRs respond to these endogenous ligands, there is a growing awareness that TLR-driven innate immune responses might precipitate severe pathophysiologic consequences even in the absence of infectious agents. APAP-induced hepatotoxicity promotes the release of mitochondrial DNA leading to TLR9 receptor activation [8,9]. While the signaling mechanisms propagated following TLR3 engagement of viral dsRNA or the synthetic dsRNA analog PolyI:C have been described in the liver [15,16], the signaling mechanism(s) evoked by endogenous factors binding to TLR3 during acute hepatotoxicity are less well understood
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