Injury Resistance in the Setting of Liver Fibrosis Is Accompanied by the Inhibition of High-Mobility Group Box-1 Translocation and Release

2017 ◽  
Vol 36 (2) ◽  
pp. 167-176 ◽  
Author(s):  
Li Bai ◽  
Waishu Jin ◽  
Ming Kong ◽  
Xiaohui Zhang ◽  
Sujun Zheng ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Immune Responses ◽  
High Mobility ◽  
Spontaneous Resolution ◽  
High Mobility Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interesting Phenomenon ◽  
Proinflammatory Mediators ◽  
Acute Insult ◽  
Acute Challenge

Background: Injury resistance occurring in the setting of liver fibrosis is an interesting phenomenon not yet well characterized. In the present study, we investigated dynamically the injury resistance against acute challenge using animal models of hepatic fibrosis and spontaneous resolution, and focused on high-mobility group box-1 (HMGB1), an important proinflammatory mediator. Methods: The hepatic damage of control, fibrosis (CCl4, 6 weeks), and regressive mice with or without CCl4 challenge was dynamically observed and compared. The translocation and release of HMGB1 were assessed by immunohistochemical staining and enzyme-linked immunosorbent assay, respectively. The gene expression of proinflammatory mediators was detected by real-time PCR. Results: Our data showed that the fibrotic mice were invulnerable to acute CCl4 insult. The injury resistance diminished along with the resolution of liver fibrosis. Acute insult triggered the translocation and release of HMGB1 in control mice, which were remarkably inhibited in fibrotic mice, even under acute challenge. Nevertheless, regressive mice exhibited obvious translocation upon insult, especially for R12d mice. HMGB1-related proinflammatory immune responses were suppressed in fibrotic mice; however, they were restored in regressive mice upon insult. Conclusion: The injury resistance in the setting of liver fibrosis is accompanied by the inhibition of HMGB1 translocation and release as well as the suppression of HMGB1-related proinflammatory immune responses.

scholarly journals Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongseok Yoo ◽  
Yunjoo Im ◽  
Ryoung-Eun Ko ◽  
Jin Young Lee ◽  
Junseon Park ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Validation Cohort ◽  
High Mobility ◽  
Kinase Domain ◽  
High Mobility Group ◽  
Rank Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Derivation Cohort ◽  
The Difference

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

scholarly journals High Mobility Group Box 1: a Novel Host Restriction Factor in Zika Virus Replication

2021 ◽  
Author(s):  
Kim-Ling Chin ◽  
Nurhafiza binti Zainal ◽  
Sing-Sin Sam ◽  
Pouya Hassandarvish ◽  
Rafidah Lani ◽  
...  
Keyword(s):  
Zika Virus ◽  
Severe Disease ◽  
High Mobility ◽  
High Mobility Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Zikv Infection ◽  
Hmgb1 Level ◽  
Antiviral Effects ◽  
Huh7 Cells

Abstract Neonatal microcephaly and adult Guillain-Barré syndrome are severe complications of Zika virus (ZIKV) infection. The robustly induced inflammatory cytokine expressions in ZIKV-infected patients may constitute a hallmark for severe disease. In the present study, the potential role of high mobility group box 1 protein (HMGB1) in ZIKV infection was investigated. HMGB1 protein expression was determined by the enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. HMGB1’s role in ZIKV infection was also explored using treatment with dexamethasone, an immunomodulatory drug. Antiviral effects of dexamethasone treatment on both wild-typed (WT) and HMGB1-knockdown (shHMGB1) Huh7 cells were determined by the focus-forming assay. Results showed that the Huh7 cells were highly susceptible to ZIKV infection. The infection was found to induce HMGB1 nuclear-to-cytoplasmic translocation, resulting in a >99% increase in the cytosolic HMGB1 expression at 72h.p.i. The extracellular HMGB1 level was elevated in a time- and multiplicity of infection (MOI)- dependent manner. Dexamethasone 150 µM treatment of the ZIKV-infected cells reduced HMGB1 extracellular release in a dose-dependent manner, with a maximum reduction of 71 ± 5.84% (p < 0.01). The treatment also reduced virus titers by over 83 ± 0.50% (p < 0.01). The antiviral effects, however, was not observed in the dexamethasone-treated HMGB1-knockdown cells, suggesting the importance of the intracellular HMGB1 in ZIKV infection. Overall, these results suggest that translocation of HMGB1 occurred during ZIKV infection and inhibition of the translocation reduced ZIKV replication. These findings highlight the potential of developing therapeutics against ZIKV infection by affecting the translocation of HMGB1 from the nucleus to the cytoplasm.

scholarly journals Astragali Radix Contributes to the Inhibition of Liver Fibrosis via High-Mobility Group Box 1-Mediated Inflammatory Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jianxia Wen ◽  
Dan Wang ◽  
Jian Wang ◽  
Ruilin Wang ◽  
Shizhang Wei ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Type I Collagen ◽  
Oral Treatment ◽  
High Mobility ◽  
High Mobility Group ◽  
Type I ◽  
Mrna Levels ◽  
Inflammatory Signaling ◽  
Astragali Radix

Astragali Radix (AR), the dried root of Astragali Radix membranaceus (Fisch.) Bge. or Astragali Radix membranaceus (Fisch.) Bge. var. mongholicus (Bge) Hsiao, is a commonly used traditional Chinese medicine for the treatment of liver diseases. This study aimed to comprehensively evaluate the pharmacological action and explore the potential mechanism of AR on liver fibrosis. Rats were administered with carbon tetrachloride for eight weeks, followed by oral treatment with AR for six weeks. The efficacy was confirmed by measuring liver function and liver fibrosis levels. The underlying mechanisms were explored by detecting the expression of related proteins. AR significantly decreased the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), collagen IV (COL-IV), hyaluronic acid (HA), laminin (LN), and precollagen type III (PCIII). In addition, AR inhibited the deposition of collagen and the activation of hepatic stellate cells. Those data strongly demonstrated that AR alleviated liver fibrosis by CCl4. In order to illustrate the potential inflammatory, the mRNA levels of IL-6, TNF-α, and IL-1β were detected. Subsequently, immunohistochemistry analysis was performed to further verify the expression of type I collagen. Finally, the expression of key proteins in the inflammatory signaling pathway was detected. AR significantly reduced the expression of high-mobility group box 1 (HMGB1), TLR4, Myd88, RAGE, and NF-κ B p65 genes and proteins. In addition, western blotting showed AR decreased the protein expression of RAGE, p-MEK1/2, p-ERK1/2, and p-c-Jun. Taken together, our data reveal that AR significantly inhibits liver fibrosis by intervening in the HMGB1-mediated inflammatory signaling pathway and secretion signaling pathway. This study will provide valuable references for the in-depth research and development of Astragali Radix against liver fibrosis.

scholarly journals Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis

2013 ◽  
Vol 20 (11) ◽  
pp. 1743-1751 ◽  
Author(s):  
Maowei Wang ◽  
Yan Yue ◽  
Chunsheng Dong ◽  
Xiaoyun Li ◽  
Wei Xu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dna Vaccine ◽  
Myocardial Injury ◽  
Flow Cytometric Analysis ◽  
High Mobility ◽  
Coxsackievirus B3 ◽  
High Mobility Group ◽  
Secretory Iga ◽  
Adjuvant Effect ◽  
Local Immunity

ABSTRACTCoxsackievirus B3 (CVB3), a small single-stranded RNA virus, belongs to thePicornaviridaefamily. Its infection is the most common cause of myocarditis, with no vaccine available. Gastrointestinal mucosa is the major entry port for CVB3; therefore, the induction of local immunity in mucosal tissues may help control initial viral infections and alleviate subsequent myocardial injury. Here we evaluated the ability of high-mobility group box 1 (HMGB1) encapsulated in chitosan particles to enhance the mucosal immune responses induced by the CVB3-specific mucosal DNA vaccine chitosan-pVP1. Mice were intranasally coimmunized with 4 doses of chitosan-pHMGB1 and chitosan-pVP1 plasmids, at 2-week intervals, and were challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 immunization alone, coimmunization with chitosan-pHMGB1 significantly (P< 0.05) enhanced CVB3-specific fecal secretory IgA levels and promoted mucosal T cell immune responses. In accordance, reduced severity of myocarditis was observed in coimmunized mice, as evidenced by significantly (P< 0.05) reduced viral loads, decreased myocardial injury, and increased survival rates. Flow cytometric analysis indicated that HMGB1 enhanced dendritic cell (DC) recruitment to mesenteric lymph nodes and promoted DC maturation, which might partly account for its mucosal adjuvant effect. This strategy may represent a promising approach to candidate vaccines against CVB3-induced myocarditis.

High-mobility group box-1 protein induce inflammatory response after pulmonary injury

2015 ◽  
Vol 3 (3) ◽  
pp. 195-214
Author(s):  
Jingxian H Golemis ◽  
Laurie J Rudensky
Keyword(s):  
Lung Injury ◽  
Inflammatory Response ◽  
Intratracheal Instillation ◽  
High Mobility ◽  
Lavage Fluid ◽  
High Mobility Group ◽  
Saline Control ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Chromosomal Protein

High-mobility group box 1 (HMGB1), a highly conserved non-histone chromosomal protein, was found to act as a potent proinflammatory cytokine and a mediator that participated in the development of systemic inflammatory response. Forty wild type C57BL/6 male (25-30gms) mice were randomly divided into three groups: saline control group; anti-HMGB1 antibody treated group and untreated group. Each group received intratracheal instillation twice per week for 4 consecutive months. 24 hours after the last exposure, anaesthetize the mice with chloral hydrate, bronchoalveolar lavage fluid was collected for cytokines analysis were measured by enzyme linked immunosorbent assay (ELISA). The level of the HMGB1 in lung tissue was determined by real-time PCR and western blot. Lung were fixed with 4% paraformaldehyde for histopathological detection. The serum level of HMGB1 increased after lung injury [peaked 2-5 hr] after lung injury, furthermore this upregulation in HMGB1 associated with increased proinflammatory cytokines [TNF-α, IL-6, IL-1β]. The injection of anti-HMGB1 antibody suppressed inflammatory reaction and improved the survival rate compared with control mice [71.3% vs. 29.4% P=0.031]

scholarly journals High-Mobility Group Protein Box-1 and its Relevance to Cerebral Ischemia

2009 ◽  
Vol 30 (2) ◽  
pp. 243-254 ◽  
Author(s):  
Qing-Wu Yang ◽  
Jing-Zhou Wang ◽  
Jing-Cheng Li ◽  
Yu Zhou ◽  
Qi-Zhong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Advanced Glycation Endproducts ◽  
High Mobility ◽  
High Mobility Group ◽  
High Mobility Group Protein ◽  
Glycation Endproducts ◽  
Extracellular Milieu ◽  
Proinflammatory Mediators ◽  
Group Protein ◽  
Therapeutic Tools

High-mobility group box-1 (HMGB1) was originally identified as a ubiquitously expressed, abundant, nonhistone DNA-binding protein. It has well-established functions in the maintenance of nuclear homeostasis. The HMGB1 can either be passively released into the extracellular milieu in response to necrotic signals or actively secreted in response to inflammatory signals. Extracellular HMGB1 interacts with receptors, including those for advanced glycation endproducts (RAGEs) as well as Toll-like receptor 2 (TLR2) and TLR4. The HMGB1 functions in a synergistic manner with other proinflammatory mediators and acts as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of diverse inflammatory and infectious disorders. Numerous reports point to HMGB1 as a novel player in the ischemic brain. This review provides an appraisal of the emerging roles of HMGB1 in cerebral ischemia injury, highlighting the relevance of HMGB1-blocking agents as potent therapeutic tools for neuroprotection.

scholarly journals High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 are significant target antigens of perinuclear anti-neutrophil cytoplasmic antibodies in autoimmune hepatitis

Gut ◽  
1999 ◽  
Vol 44 (6) ◽  
pp. 867-873 ◽  
Author(s):  
J Sobajima ◽  
S Ozaki ◽  
H Uesugi ◽  
F Osakada ◽  
M Inoue ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Hepatitis B ◽  
Autoimmune Hepatitis ◽  
Chronic Hepatitis C ◽  
Chronic Hepatitis B ◽  
High Mobility ◽  
High Mobility Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chromosomal Proteins

BACKGROUNDHigh mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 have been identified as novel antigens of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs), and the existence of anti-HMG1 and anti-HMG2 antibodies in a population of patients with ulcerative colitis has been reported.AIMSTo investigate whether HMG1 and HMG2 are target antigens for p-ANCAs in autoimmune hepatitis (AIH).PATIENTSSerum samples from 28 patients with AIH, 44 patients with primary biliary cirrhosis (PBC), 27 patients with chronic hepatitis C, and 23 patients with chronic hepatitis B were tested.METHODSANCAs were detected by routine indirect immunofluorescence (IIF). Anti-HMG1 and anti-HMG2 antibodies were assayed by enzyme linked immunosorbent assay.RESULTSp-ANCAs were detected in 89% (25/28) of patients with AIH, 36% (16/44) of patients with PBC, 11% (3/27) of patients with chronic hepatitis C, and 13% (3/23) of patients with chronic hepatitis B. Anti-HMG1 and/or anti-HMG2 antibodies were detected in 89% (25/28) of patients with AIH, 70% (31/44) with PBC, 26% (7/27) with chronic hepatitis C, and 9% (2/23) with chronic hepatitis B. In AIH, anti-HMG1 and/or anti-HMG2 antibodies were detected in 96% (24/25) of p-ANCA positive patients. The p-ANCA staining pattern detected by IIF using sera from patients with AIH disappeared or decreased in titre after preincubation with a mixture of HMG1/HMG2. The presence and titres of those antibodies in AIH correlated significantly with those of p-ANCA, but not with those of anti-nuclear antibody or anti-smooth muscle antibody.CONCLUSIONSHMG1 and HMG2 are significant target antigens of p-ANCA in AIH.

scholarly journals Leukocyte-derived High-mobility group box 1 controls innate immune responses against Listeria monocytogenes

2019 ◽  
Author(s):  
Annika Volmari ◽  
Katharina Foelsch ◽  
Karsten Yan ◽  
Minyue Qi ◽  
Karlotta Bartels ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Immune Responses ◽  
Tissue Injury ◽  
Myeloid Cells ◽  
High Mobility ◽  
Severe Infection ◽  
High Mobility Group ◽  
Inflammatory Monocyte ◽  
Bacterial Dissemination ◽  
Monocyte Recruitment

AbstractHigh-mobility group box 1 (HMGB1) is a damage-associated molecular pattern with key proinflammatory functions following tissue injury. Moreover, HMGB1 neutralization was shown to alleviate LPS-induced shock, suggesting a role for the protein as a master therapeutic target for inflammatory and infectious diseases. Here, we report that HMGB1 neutralization impedes immune responses to Listeria monocytogenes, a wide-spread bacterium with pathogenic relevance for humans and rodents. Using genetic deletion strategies and neutralizing antibodies, we demonstrate that hepatocyte HMGB1, a major driver of post-necrotic inflammation in the liver, is dispensable for pathogen defense during moderately severe infection with listeria. In contrast, antibody-mediated HMGB1 neutralization and HMGB1 deficiency in myeloid cells effectuate rapid and uncontrolled bacterial dissemination in mice despite preserved basic leukocyte functionality and autophagy induction. During overwhelming infection, hepatocyte injury may contribute to increased HMGB1 serum levels and excessive inflammation in the liver, supporting context-dependent roles for HMGB1 from different cellular compartments during infection. We provide mechanistic evidence that HMGB1 from circulating immune cells contributes to the timely induction of hepatic immune regulatory gene networks, early inflammatory monocyte recruitment to the liver and promotion of neutrophil survival, which are mandatory for pathogen control. In summary, our data establish HMGB1 as a critical co-factor in the immunological clearance of listeria, and argue against HMGB1 neutralization as a universal therapeutic strategy for sepsis.Author summaryHigh-mobility group box 1 (HMGB1) is an abundantly expressed nucleoprotein with signaling properties following secretion or release into the extracellular space. Given its central immune-regulatory roles during tissue injury and LPS-induced septic shock, interventions aimed at HMGB1 signaling have been advocated as therapeutic options for various disease conditions. Here, we show that antibody-mediated HMGB1 neutralization interferes with immunological defense against Listeria monocytogenes, a gram-positive bacterium with high pathogenic relevance for rodents and humans, effectuating uncontrolled bacterial growth and inflammation. Using conditional knockout animals, we demonstrate that while leukocyte functionality is preserved in HMGB1-deficient myeloid cells, HMGB1 released in response to Listeria triggers hepatic inflammatory monocyte recruitment and activation of transcriptional immune networks required for the early control of bacterial dissemination. Hepatocyte HMGB1, a key driver of post-necrotic inflammation in the liver, is dispensable for the immune response during moderately severe infection, but likely contributes to excessive hepatitis when infection is uncontrolled and cellular injury is high. We demonstrate a critical and non-redundant role for HMGB1 in the immune-mediated clearance of listeriosis and argue against HMGB1 neutralization as a universal therapeutic option in the context of infection.

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