title: Toll like receptor 3 plays a critical role in the progression and severity of acetaminophen-induced hepatotoxicity.
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.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America. kcavassa@med.umich.edu
authors.forename: Karen A
authors.initials: KA
authors.lastname: Cavassani
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Moreira
authors.forename: David
authors.initials: D
authors.lastname: Habiel
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Ana Lucia
authors.initials: AL
authors.lastname: Coelho
authors.forename: Ron M
authors.initials: RM
authors.lastname: Allen
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Janna
authors.initials: J
authors.lastname: Raphelson
authors.forename: William F
authors.initials: WF
authors.lastname: Carson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D010766:Phosphorylation; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D018925:Chemokines; D008024:Ligands; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases