HMGB1, a potent proinflammatory cytokine in sepsis

Huang, Wenli; Tang, Ya‐Bin; Li, Lei

doi:10.1016/j.cyto.2010.02.021

Cited by 203 publications

(156 citation statements)

References 120 publications

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“…However, from studies in animal models of sepsis, it has now become clear that HMGB1 secreted from macrophages and DCs acts as a key cytokine to stimulate a sustained inflammation and organ damage (10,11). Serum HMGB1 is also elevated in human sepsis (12), although its role in sepsis pathogenesis remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Although therapy to suppress the immediate cytokine response, such as treatment with TNF and IL-1β antibodies, have failed in clinical trials (4)(5)(6), it has now come to be recognized that, at least in animal models, high-mobility group protein 1 (HMGB1), which is secreted from macrophages and dendritic cells (DCs) but not lymphocytes late in the disease, acts as a master regulator of late and sustained cytokine storm, upregulating many cytokines including TNF-α, IL-6, IL-1β, and IL-8 (reviewed in refs. [7][8][9][10][11]. In fact, injection of mice with HMGB1 is enough to induce the lethal organ damage seen in sepsis (12), whereas treatment with neutralizing HMGB1 antibody can rescue mice and rats from experimental sepsis (13,14).…”

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confidence: 99%

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Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Choi

Abraham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsisinduced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ −/− mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ −/− mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ −/− mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Choi

Abraham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…We first showed direct evidence that acteoside contributes to the reduction of HMGB1 and NO production by inducing HO-1 in macrophages. Other studies suggested that HMGB1 mediates cognitive impairment in sepsis survivors (Chavan et al, 2012;Huang et al, 2010) and that HO-1 inhibits the release of HMGB1 in Raw264.7 cells activated by LPS and in LPS-or CLP-induced septic mice (Tsoyi et al, 2009). Next, we assessed the signaling pathway through which acteoside induces HO-1.…”

Section: Discussionmentioning

confidence: 92%

Acteoside Improves Survival in Cecal Ligation an Puncture-Induced Septic Mice via Blocking of High Mobility Group Box 1 Release

Seo

Pak

et al. 2013

Molecules and Cells

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Acteoside, an active phenylethanoid glycoside, has been used traditionally as an anti-inflammatory agent. The molecular mechanism by which acteoside reduces inflammation was investigated in lipopolysaccharide (LPS)-induced Raw264.7 cells and in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. In vitro, acteoside inhibits high mobility group box 1 (HMGB1) release and iNOS/NO production and induces heme oxygenase-1 (HO-1) expression in a concentration-dependent manner, while HO-1 siRNA antagonizes the inhibition of HMGB1 and NO. The effect of acteoside is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and Nfr2 siRNA, indicating that acteoside induces HO-1 via p38 MAPK and NF-E2-related factor 2 (Nrf2). In vivo, acteoside increases survival and decreases serum and lung HMGB1 levels in CLP-induced sepsis. Overall, these results that acteoside reduces HMGB1 release and may be beneficial for the treatment of sepsis.

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“…The B box domain is responsible for proinflammatory activity of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis (Huang et al, 2010). Many recent studies demonstrated that HMGB1 played a pivotal role in cardiovascular diseases, such as atherosclerosis, myocardial ischemia/reperfusion injury (IRI), heart failure, and myocardial infarction.…”

Section: Hmgb1mentioning

confidence: 99%

Inflammation and Genetics of Inflammation in Cardiovascular Diseases

Bucová¹

2011

Angina Pectoris

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HMGB1, a potent proinflammatory cytokine in sepsis

Cited by 203 publications

References 120 publications

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Acteoside Improves Survival in Cecal Ligation an Puncture-Induced Septic Mice via Blocking of High Mobility Group Box 1 Release

Inflammation and Genetics of Inflammation in Cardiovascular Diseases

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