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

ABSTRACT: The 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.

SUBMITTER: Yoo H

PROVIDER: S-EPMC8097071 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Reversing established sepsis with antagonists of endogenous high-mobility group box 1.

Project description:Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1beta] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1beta. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 microg per mouse) or the DNA-binding A box (600 microg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.

| S-EPMC314179 | biostudies-literature

Associations between Single Nucleotide Polymorphisms of High Mobility Group Box 1 Protein and Clinical Outcomes in Korean Sepsis Patients.

Project description:PurposeHigh mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock.Materials and methodsWe enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured.ResultsThe proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1β, IL-6, IL-10, IL-17, and tumor necrosis factor-α] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival.ConclusionThe variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions.

| S-EPMC4696941 | biostudies-literature

Association of serum high-mobility group box protein 1 level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

Project description:Background and objectiveHigh-mobility group box 1 (HMGB1) protein is important in acute lung injury. However, the role of HMGB-1 in acute exacerbation of fibrosing interstitial pneumonia (AE-FIP) has not been adequately studied.MethodsWe prospectively measured serum HMGB1 level from disease onset to day 7 in 36 patients with AE-FIP6 patients had missing data because of early death (within 7 days). We then examined the association of HMGB1 level and outcome, and the associations of rhTM with HMGB1 level and outcome in 19 patients who were treated with rhTM (rhTM group) and 11 patients who were not (control group).ResultsData from 36 AE-FIP patients (mean age, 73.5±6.7years) were analyzed. Serum HMGB1 level was significantly higher in patients with AE-FIP than in those with stable idiopathic pulmonary fibrosis (16.4±13.5 vs 5.7±2.6 ng/ml, respectively; p = 0.003). HMGB1 was significantly lower on day 7 than at AE-FIP onset in survivors (6.5±4.8 vs 14.7±12.9 ng/ml, respectively; p = 0.02) but not in nonsurvivors (14.6±10.5 vs 9.2±4.8 ng/ml, respectively; p = 0.08). Although HMGB1 level at day 7 was significantly lower after rhTM treatment than at AE-FIP onset (8.4±6.1 vs 15.2±12.5 ng/ml, respectively; p = 0.02), it did not significantly decrease in patients receiving treatments other than rhTM (11.3±11.3 vs 8.3±5.3 ng/ml, respectively; p = 0.37). Three-month survival was 60.0% in the rhTM group and 36.4% in the control group (p = 0.449). In multivariate analysis, a decrease in HMGB1 was a significant independent predictor of 3-month survival (Odds ratio, 12.4; p = 0.007).ConclusionrhTM lowers serum HMGB1 level and may improve survival after AE-FIP. HMGB1 may be a promising therapeutic target for AE-FIP.

| S-EPMC5967827 | biostudies-literature

Chronic kidney disease worsens sepsis and sepsis-induced acute kidney injury by releasing High Mobility Group Box Protein-1.

Project description:We have shown that folate-induced kidney dysfunction and interstitial fibrosis predisposes mice to sepsis mortality. Agents that increase survival in normal septic mice were ineffective in a two-stage kidney disease model. Here we used the 5/6 nephrectomy mouse model of progressive chronic kidney disease (CKD) to study how CKD affects acute kidney injury (AKI) induced by sepsis. We induced sepsis using cecal ligation and puncture and found that the presence of CKD intensified the severity of kidney and liver injury, cytokine release, and splenic apoptosis. Accumulation of High Mobility Group Box Protein-1 (HMGB1; a late proinflammatory cytokine released from apoptotic cells), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-?, interleukin (IL)-6, or IL-10 was increased in CKD or sepsis alone and to a greater extent in CKD-sepsis. Only part of the increase was explained by decreased renal clearance. Surprisingly, we found splenic apoptosis in CKD, even in the absence of sepsis. Although VEGF neutralization with soluble fms-like tyrosine kinase 1 (sFLT-1) (a soluble VEGF receptor) effectively treated sepsis, it was ineffective against CKD-sepsis. A single dose of HMGB1-neutralizing antiserum administered 6?h after sepsis alone was ineffective; however, CKD-sepsis was attenuated by anti-HMGB1. Splenectomy transiently decreased circulating HMGB1 levels, reversing the effectiveness of anti-HMGB1 treatment on CKD-sepsis. Thus, progressive CKD increases the severity of sepsis, in part, by reducing the renal clearance of several cytokines. CKD-induced splenic apoptosis and HMGB1 release could be important common mediators for both CKD and sepsis.

| S-EPMC3491658 | biostudies-literature

Glutathione S-Transferase Pi Prevents Sepsis-Related High Mobility Group Box-1 Protein Translocation and Release.

Project description:Glutathione S-transferase Pi (GSTP) was originally identified as one of cytosolic phase II detoxification enzymes and also was considered to function via its non-catalytic, ligand-binding activity. We have reported that GSTP played an anti-inflammatory role in macrophages, suggesting that GSTP may have a protective role in inflammation. In this study, we deleted the murine Gstp gene cluster and found that GSTP significantly decreased the mortality of experimental sepsis and reduced related serum level of high mobility group box-1 protein (HMGB1). As HMGB1 is the key cytokine involved in septic death, we further studied the effect of GSTP on HMGB1 release. The results demonstrated that a classic protein kinase C (cPKC) dependent phosphorylation of cytoplasmic GSTP at Ser184 occurred in macrophages in response to lipopolysaccharide (LPS) stimulation. Phosphorylated GSTP was then translocated to the nucleus. In the nucleus, GSTP bound to HMGB1 and suppressed LPS-triggered and cPKC-mediated HMGB1 phosphorylation. Consequently, GSTP prevented the translocation of HMGB1 to cytoplasm and release. Our findings provide the new evidence that GSTP inhibited HMGB1 release via binding to HMGB1 in the nucleus independent of its transferase activity. cPKC-mediated GSTP phosphorylation was essential for GSTP to translocate from cytoplasm to nucleus. To our knowledge, we are the first to report that nuclear GSTP functions as a negative regulator to control HMGB1 release from macrophages and decreases the mortality of sepsis.

| S-EPMC5827551 | biostudies-literature

High Mobility Group Box 1 in Human Cancer.

Project description:High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational modifications that promote its translocation to the cytosol, from where it is released extracellularly, either actively or passively, according to cell type and stressor. In the extracellular milieu, HMGB1 triggers innate inflammatory responses that may be beneficial or harmful, depending on the magnitude and duration of release of this pro-inflammatory protein at sites of tissue injury. Heightened awareness of the potentially harmful activities of HMGB1, together with a considerable body of innovative, recent research, have revealed that excessive production of HMGB1, resulting from misdirected, chronic inflammatory responses, appears to contribute to all the stages of tumorigenesis. In the setting of established cancers, the production of HMGB1 by tumor cells per se may also exacerbate inflammation-related immunosuppression. These pro-inflammatory mechanisms of HMGB1-orchestrated tumorigenesis, as well as the prognostic potential of detection of elevated expression of this protein in the tumor microenvironment, represent the major thrusts of this review.

| S-EPMC7407638 | biostudies-literature

RNA sequencing of high mobility group box 1-treated melanocytes [hmgb1]

Project description:Purpose: Determine the mechanism of high mobility group box 1 (HMGB1)-induced signaling in melanocytes. Method: Primary human epidermal melanocytes were treated with HMGB1 (1 μg/ml) and incubated for 24 h. Total RNA (500 ng) from melanocytes were extracted and subjected to library synthesis. Results: HMGB1-treated melanocytes exhibited upregulation of cell death and type 1 interferon-related genes. Conclusion: HMGB1-induced melanocyte signaling was well evaluated using RNA sequencing.

2023-07-28 | GSE216423 | GEO

High-mobility-group box nuclear factors of Plasmodium falciparum.

Project description:In eukaryotes, the high-mobility-group (HMG) nuclear factors are highly conserved throughout evolution and are divided into three families, including HGMB, characterized by an HMG box domain. Some HMGB factors are DNA structure specific and preferentially interact with distorted DNA sequences, trigger DNA bending, and hence facilitate the binding of nucleoprotein complexes that in turn activate or repress transcription. In Plasmodium falciparum, two HMGB factors were predicted: PfHMGB1 and PfHMGB2. They are small proteins, under 100 amino acids long, encompassing a characteristic HMG box domain closely related to box B of metazoan factors, which comprises two HMG box domains, A and B, in tandem. Computational analyses supported the conclusion that the Plasmodium proteins were genuine architectural HMGB factors, and in vitro analyses performed with both recombinant proteins established that they were able to interact with distorted DNA structures and bend linear DNA with different affinities. These proteins were detected in both asexual- and gametocyte-stage cells in Western blotting experiments and mainly in the parasite nuclei. PfHMGB1 is preferentially expressed in asexual erythrocytic stages and PfHMGB2 in gametocytes, in good correlation with transcript levels of expression. Finally, immunofluorescence studies revealed differential subcellular localizations: both factors were observed in the nucleus of asexual- and sexual-stage cells, and PfHMGB2 was also detected in the cytoplasm of gametocytes. In conclusion, in light of differences in their levels of expression, subcellular localizations, and capacities for binding and bending DNA, these factors are likely to play nonredundant roles in transcriptional regulation of Plasmodium development in erythrocytes.

| S-EPMC1459676 | biostudies-literature

High-Mobility Group Box 1 in Dry Eye Inflammation.

Project description:PurposeTo determine high-mobility group box 1 (HMGB1) expression during experimental dry eye (EDE) and dry eye-like culture conditions and elucidate its role in corneal dry eye-related inflammation.MethodsEDE was induced in 8- to 12-week-old C57BL/6 mice. Corneal tissue sections and lysates from EDE and untreated mice were evaluated for HMGB1 expression by immunostaining and quantitative real-time PCR (qPCR). For in vitro studies, human corneal epithelial cells (HCEC) were treated with hyperosmolar media, toll-like receptor (TLR) agonists, or proinflammatory cytokines to determine HMGB1 expression. HCEC were also treated with human recombinant HMGB1 (hrHMGB1) alone or in combination with inflammatory stimuli, and TNFα, IL-6, and IL-8 expression evaluated by qPCR and ELISA. Nuclear factor-κB (NF-κB) p65 nuclear translocation was determined by immunostaining.ResultsEDE mice had higher corneal HMGB1 RNA and protein expression compared to untreated animals. In HCEC, hyperosmolar stress and TNFα treatment stimulated HMGB1 production and secretion into culture supernatants. However, in vitro stimulation with hrHMGB1 did not induce secretion of TNFα, IL-6, or IL-8 or NF-κB p65 nuclear translocation. In addition, the inflammatory response elicited by TLR agonists fibroblast-stimulating lipopeptide-1 and lipopolysaccharide was not enhanced by hrHMGB1 treatment.ConclusionsHMGB1 expression was enhanced by dry eye conditions in vivo as well as in vitro, during hyperosmolar stress and cytokine exposure, suggesting an important role for HMGB1 in dry eye disease. However, no direct inflammatory effect was observed with HMGB1 treatment. Therefore, under these conditions, HMGB1 does not contribute directly to dry eye-induced inflammation and its function at the ocular surface needs to be explored further.

| S-EPMC5886030 | biostudies-literature

Association of chromatin proteins high mobility group box (HMGB) 1 and HMGB2 with mitotic chromosomes.

Project description:High mobility group box (HMGB) 1 and 2 are two abundant nonhistone nuclear proteins that have been found in association with chromatin. Previous studies based on immunofluorescence analysis indicated that HMGB1 dissociates from chromosomes during mitosis. In the present work, HMGB1 and 2 subcellular localization was reinvestigated in living cells by using enhanced green fluorescent protein- and Discosome sp. red fluorescent protein-tagged proteins. Contrary to previous reports, HMGB1 and 2 were shown to be present under two forms in mitotic cells, i.e., free and associated with the condensed chromatin, which rapidly exchange. A detailed analysis of HMGB2 interaction with mitotic chromosomes indicated that two sites encompassing HMG-box A and B are responsible for binding. Importantly, this interaction was rapidly inactivated when cells were permeabilized or exposed to chemical fixatives that are widely used in immunodetection techniques. A comparable behavior was also observed for two proteins of the HMG-nucleosome binding (HMGN) group, namely, HMGN1 and HMGN2.

| S-EPMC181577 | biostudies-other

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