Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure

Fisher, James E.; McKenzie, Travis J.; Lillegard, Joseph B.; Yu, Yue; Juskewitch, Justin E.; Nedredal, Geir I.; Brunn, Gregory J.; Yi, Eunhee S.; Malhi, Harmeet; Smyrk, Thomas C.; Nyberg, Scott L.

doi:10.1016/j.jss.2012.11.051

Cited by 73 publications

(62 citation statements)

References 36 publications

(55 reference statements)

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“…6 Subsequently, in CCL4 and concanavalin A models, CD11b 1 F4/80 1 or F4/80 -or CD11b/CD163 inflammatory macrophages were found to be remarkably increased and Infiltration of these macrophages in liver contributed to massive liver damage. [32][33][34][35] Activated macrophages phagocytose the products and secrete ROS, and an excess of ROS may contribute to ongoing liver injury. 8,9 In the present study, despite an increase in macrophage numbers in ALF-E, ROS production was low, indicating significant functional impairment and deactivation of macrophages in patients with HEV infection.…”

Section: Discussionmentioning

confidence: 99%

“…There were significant differences in the ALT, aspartate aminotransferase (AST), bilirubin, and INR values in ALF-E(P) and in AVH-E(P) patients compared to HC(P) ( Table 1). All patients in the ALF-E(P) group were detected during late pregnancy in the third trimester (week 32; range, weeks [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. None of the AVH-E patients developed HE during the follow-up period.…”

Section: Alf-e Versus Avh-e Versus Healthy Pregnantmentioning

confidence: 99%

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Impaired monocyte‐macrophage functions and defective toll‐like receptor signaling in hepatitis E virus‐infected pregnant women with acute liver failure

et al. 2015

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Acute viral hepatitis resulting due to hepatitis E viral infection (AVH-E) is often serious in pregnancy and could result in acute liver failure (ALF). The role of monocytes and macrophages (mono-macs) in the pathogenesis of AVH-E and development of ALF-E in pregnancy is unclear. We investigated the functions of mono-macs in pregnant (P), AVH-E (n 5 44), ALF-E (n 5 12), healthy controls (HC; n 5 20) and compared with nonpregnant (NP) AVH-E (n 5 10), ALF-E (n 5 5), and HC (n 5 10). We also recruited non-hepatitis E virus-related pregnant (P), ALF-NE (n 5 5) and non-pregnant (NP), ALF-NE (n 5 12) patients with ALF. Mono-macs, dendritic cell (DC) phenotypes, and Toll-like receptor (TLR) expressions were studied by flow cytometry and reverse-transcriptase polymerase chain reaction. Mono-macs functionality was determined by analyzing their phagocytic activity and reactive oxygen species (ROS) generation by using flow cytometry. Frequency of mono-macs and DCs was increased during HEV infection compared to HC (P < 0.001). Macrophages were increased (P < 0.002) in ALF-E(P) compared to ALF-NE(P). The macrophage phagocytic activity and Escherichia coli-induced ROS production was significantly impaired in ALF-E(P) compared to AVH-E(P) (P < 0.001), ALF-E(NP), and ALF-NE(P) patients (P < 0.02). TLR3 and TLR9 expression and downstream MYD88 signalling molecules IRF3 and IRF7 were significantly down-regulated in ALF-E(P) (P < 0.00) compared to AVH-E(P) and ALF-NE(P). Conclusion: Functionality of mono-macs is impaired in pregnant ALF-E patients compared to AVH-E(P). Reduced TLR3 and TLR7 expression and TLR downstream-signaling molecules in pregnant ALF-E patients suggests inadequate triggers for the innate immune responses contributing to development and severity of ALF-E. Studies using TLR agonists to activate mono-macs may be of use and in vitro studies should be undertaken using patient samples. (HEPATOLOGY

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Section: Discussionmentioning

confidence: 99%

Section: Alf-e Versus Avh-e Versus Healthy Pregnantmentioning

confidence: 99%

Impaired monocyte‐macrophage functions and defective toll‐like receptor signaling in hepatitis E virus‐infected pregnant women with acute liver failure

et al. 2015

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“…The chances of survival for advanced ALF are needed for liver transplantation [1, 2]. The mouse models of APAP-induced liver injury and clinical translational studies revealed that APAP-induced liver damage is not only influenced by the dose of APAP and the initial hepatocyte injury but also by the inflammatory response, which is recognized by activating hepatic macrophages (Kupffer cells) and neutrophils [3, 4]. …”

Section: Introductionmentioning

confidence: 99%

Blockade of Notch signaling promotes acetaminophen-induced liver injury

Jiang

Ke²,

Shi

et al. 2017

Immunol Res

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Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS. Some animals were injected with γ-secretase inhibitor DAPT or DMSO vehicle. For the in vitro study, bone marrow-derived macrophages (BMMs) were transfected with Notch1 siRNA, TLR4 siRNA, and non-specific (NS) siRNA and stimulated with LPS. Indeed, paracetamol/acetaminophen-induced liver damage was worse after Notch blockade with DAPT in wild-type mice, which was accompanied by significantly increased ALT levels, diminished hairy and enhancer of split-1 (Hes1), phosphorylated Stat3 and Akt but enhanced high mobility group box 1 (HMGB1), TLR4, NF-κB, and NLRP3 activation after APAP challenge. Mice receiving DAPT increased macrophage and neutrophil accumulation and hepatocellular apoptosis. However, TLR4 KO mice received DAPT reduced APAP-induced liver damage, NF-κB, NLRP3, and cleaved caspase-1 activation. BMMs transfected with Notch1 siRNA reduced Hes1, phosphorylated Stat3 and Akt but augmented HMGB1, TLR4, NF-κB, and NLRP3. Furthermore, TLR4 siRNA knockdown resulted in decreased NF-κB, NLRP3, cleaved caspase-1, and IL-1β levels following LPS stimulation. These results demonstrate that Notch signaling regulates innate NLRP3 inflammasome activation through regulation of HMGB1/TLR4/NF-κB activation in APAP-induced liver injury. Our novel findings underscore the critical role of the Notch1-Hes1 signaling cascade in the regulation of innate immunity in APAP-triggered liver inflammation. This might imply a novel therapeutic potential for the drug-induced damage-associated lethal hepatitis.

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“…Subsequently, it leads to the formation of free radicals and the activation of Kupffer cells, which cause centrilobular apoptosis and necrosis [8]. Proinﬂammatory cytokines and the innate immune system were considered to mediate the acetaminophen-induced liver injuries [20,21,22]. The course of regeneration after acetaminophen-induced injury is similar to that in the CCl 4 model.…”

Section: Toxin Injury Modelsmentioning

confidence: 99%

Rodent Models and Imaging Techniques to Study Liver Regeneration

Wei

Dirsch²,

McLean³

et al. 2014

Eur Surg Res

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The liver has the unique capability of regeneration from various injuries. Different animal models and in vitro methods are used for studying the processes and mechanisms of liver regeneration. Animal models were established either by administration of hepatotoxic chemicals or by surgical approach. The administration of hepatotoxic chemicals results in the death of liver cells and in subsequent hepatic regeneration and tissue repair. Surgery includes partial hepatectomy and portal vein occlusion or diversion: hepatectomy leads to compensatory regeneration of the remnant liver lobe, whereas portal vein occlusion leads to atrophy of the ipsilateral lobe and to compensatory regeneration of the contralateral lobe. Adaptation of modern radiological imaging technologies to the small size of rodents made the visualization of rodent intrahepatic vascular anatomy possible. Advanced knowledge of the detailed intrahepatic 3D anatomy enabled the establishment of refined surgical techniques. The same technology allows the visualization of hepatic vascular regeneration. The development of modern histological image analysis tools improved the quantitative assessment of hepatic regeneration. Novel image analysis tools enable us to quantify reliably and reproducibly the proliferative rate of hepatocytes using whole-slide scans, thus reducing the sampling error. In this review, the refined rodent models and the newly developed imaging technology to study liver regeneration are summarized. This summary helps to integrate the current knowledge of liver regeneration and promises an enormous increase in hepatological knowledge in the near future. © 2014 S. Karger AG, Basel

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Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure

Cited by 73 publications

References 36 publications

Impaired monocyte‐macrophage functions and defective toll‐like receptor signaling in hepatitis E virus‐infected pregnant women with acute liver failure

Impaired monocyte‐macrophage functions and defective toll‐like receptor signaling in hepatitis E virus‐infected pregnant women with acute liver failure

Blockade of Notch signaling promotes acetaminophen-induced liver injury

Rodent Models and Imaging Techniques to Study Liver Regeneration

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