Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

Chen, Ruochan; Hou, Wen Chi; Zhang, Liqun; Kang, Rui; Xue, Fan; Tang, Daolin

doi:10.2119/molmed.2013.00099

Cited by 88 publications

(75 citation statements)

References 117 publications

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“…The paradigm of TNF‐α and HMGB1 regulation reillustrated the importance of TNF‐α in cell‐transplantation–induced inflammation. Recently, considerable information has accumulated about the role of HMGB1 in I/R and other liver injuries . Rapid rise in serum HMGB1 after cell transplantation was in agreement with liver injury, perhaps destruction of less‐viable transplanted cells, and TNF‐α/HMGB1 interaction.…”

Section: Discussionmentioning

confidence: 96%

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

et al. 2014

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Engraftment of transplanted cells is critical for liver-directed cell therapy but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells. To define whether TNF-α served roles in cell-transplantation-induced hepatic inflammation, we used TNF-α antagonist, etanercept, for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas etanercept prior to cell transplantation essentially normalized these responses. Moreover, ETN downregulated cell transplantation-induced intrahepatic release of secretory cytokines, such as high mobility group box 1. These effects of etanercept decreased cell transplantation-induced activation of neutrophils but not of Kupffer cells. Transplanted cell engraftment improved by several-fold in etanercept-treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with etanercept before multiple cell transplantation sessions. Transplanted cell numbers did not change over time indicating absence of cell proliferation after etanercept alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after etanercept pretreatment significantly accelerated liver repopulation compared with control rats. We concluded that TNF-α played a major role in orchestrating cell transplantation-induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. As TNF-α antagonism by etanercept decreased transplanted cell clearance, improved cell engraftment and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy.

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Section: Discussionmentioning

confidence: 96%

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

et al. 2014

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“…Macrophage-derived HMGB1 was shown to mediate acute inflammatory response and endotoxin lethality during acute lung injury in mice [35, 36]. HMGB1 can also be actively released by innate immune cells and contribute to innate immune response in APAP-induced liver injury [37, 38], suggesting its role as an endogenous danger signal or alarmin that may engage a diverse receptor repertoire, including TLR2, TLR4, and advanced glycation end products (RAGE), for the initiation of an array of inflammatory responses [39]. Consistent with these findings, our current data revealed that blocking Notch signaling by DAPT resulted in enhanced TLR4 activation, which is crucial for triggering innate immune response.…”

Section: Discussionmentioning

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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“…In addition to liver I/R (Bamboat et al, 2010; Cai et al, 2013; Cardinal et al, 2009; Dhupar et al, 2011; Evankovich et al, 2010; Huang et al, 2013a; Izuishi et al, 2006; Kang et al, 2011a; Li et al, 2013a; Liu et al, 2013b; Nace et al, 2013; Ogiku et al, 2011; Oishi et al, 2012; Tsung et al, 2005; Watanabe et al, 2005; Zeng et al, 2009), transplantation (Ilmakunnas et al, 2008; Kao et al, 2008) and hepatocyte regeneration (Ogiku et al, 2011; Yang et al, 2012g; Zhou et al, 2011b) (discussed above), HMGB1 is implicated in several liver diseases (discussed below) (Chen et al, 2013c). …”

Section: Hmgb1 and Diseasementioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

Cited by 88 publications

References 117 publications

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

Blockade of Notch signaling promotes acetaminophen-induced liver injury

HMGB1 in health and disease

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