Inflammatory response and immune regulation of high mobility group box—1 protein

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ABSTRACT： Sepsis is an infection induced systemic inflammatory response syndrome and is a major cause of morbidity as well as mortality in intensive care units. A growing body of evidence suggests that the activation of a proinflammatory cascade is responsible for the development of immune dysfunction， susceptibility to severe sepsis and septic shock. The present theories of sepsis as a dysregulated inflammatory response and immune function， as manifested by excessive release of inflammatory mediators such as high mobility group box 1 protein （HMGB1）， are supported by increasing studies employing animal models and clinical observations of sepsis. HMGB1， originally described as a DNA-binding protein and released passively by necrotic cells and actively by macrophages/monocytes， has been discovered to be one of essential cytokines that mediates the response to infection， injury and inflammation. A growing number of studies still focus on the inflammation-regulatory function and its contribution to infectious and inflammatory disorders， recent data suggest that HMGB1 formation can also markedly influence the host cell-mediated immunity， including T lymphocytes and macrophages. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of septic complications， and discuss the therapeutic potential of several HMGB1-targeting agents in experimental sepsis. In addition， with the development of traditional Chinese medicine in recent years， it has been proven that traditional Chinese herbal materials and their extracts have remarkable effective in treating severe sepsis. In this review， we therefore provide some new concepts of HMGB1-targeted Chinese herbal therapies in sepsis.

KEY WORDS： Sepsis； Inflammatory mediators； High mobility group box 1 protein

World J Emerg Med 2010；1（2）：93-98

INTRODUCTION

Sepsis is defined as a clinical syndrome characterized by a severe infection， encompassing fever， leukocytosis/leukopenia， elevated cardiac output， and reduced systemic vascular resistance. Initiated by an infection， sepsis is due to excessive systemic inflammatory response induced by accumulation of various proinflammatory cytokines.[1，2] By bacterial toxins [e.g.， lipopolysaccharide （LPS）]， macrophages/monocytes release nitric oxide and various cytokines such as tumor necrosis factor （TNF）-α， interleukin （IL）-1， interferon-γ， and macrophage migration inhibitory factor， which individually or in combination， give rise to the immunologic derangement of severe sepsis or septic shock.[3] However， the early release of TNF-α makes it difficult to target therapeutically in a clinical setting，[3] prompting the search into late proinflammatory cytokines that may offer a wider therapeutic window for the treatment of severe sepsis or septic shock.

A high mobility group box-1 protein （HMGB1） released by activated macrophages/monocytes functions as a late mediator of lethal endotoxemia and sepsis.[4-8] Moreover， administration of anti-HMGB1 antibodies or inhibitors [e.g.， ethyl pyruvate （EP）， nicotine， or stearoyl lysophosphatidylcholine] significantly protects mice against LPS-induced acute lung injury[9] and lethal endotoxemia.[4，7，10] Notably， these anti-HMGB1 reagents are capable of preventing mice from lethal experimental sepsis even when the first doses are given 24 hours after the onset of sepsis， indicating a wider window for HMGB1-targeted therapeutic measurement.[6，7，11] Therefore， agents proven clinically safe and yet still capable of attenuating HMGB1 release may be potentially active in the prevention and treatment of septic complications.

HMGB1 as a late mediator of inflammatory response

A number of investigations have been conducted to treat sepsis by targeting early proinflammatory cytokines including TNF-α. Although these approaches have led to successful therapies for rheumatoid arthritis and Crohn's disease， they have not been proven effective in the treatment of severe sepsis or septic shock. A major obstacle in targeting TNF-α or other cytokines in the treatment of sepsis is that most of these cytokines are released at the early stage of infection， usually within hours after the exposure to septic challenge. This fast kinetic pattern does not provide sufficient time for the administration in clinical settings despite the successful results in experimental animal models. It is the fact that death in sepsis may occur long after the systemic levels of proinflammatory cytokines have become normal， which prompted Tracey et al to systematically search for the undiscovered mediators of septic lethality.[4]

HMGB1 could be detected in the cell supernatant at time points later than 8 hours after LPS stimulation， peaking at 18 hours. In mice challenged with LPS or TNF-α， HMGB1 could be released from serum samples after 8-32 hours. Recombinant HMGB1 generated in Escherichia coli was lethal to both LPS-sensitive and LPS-resistant mice when injected intraperitoneally， demonstrating that the effect was not caused by LPS contamination. The administration of HMGB1 resulted in fever， weight loss， piloerection， shivering and microthrombi formation in the liver and lungs. It also caused an increase in circulating TNF-α level in vivo. Thus extracellular HMGB1 seems to have a remarkable proinflammatory effect. In addition， HMGB1 is not only released in response to proinflammatory stimuli， but itself induces the production of inflammatory mediators by macrophages and neutrophils.[12，13] HMGB1 treatment of macrophages induces de novo synthesis of TNF-α， as mRNA expression is also increased. The exposure of HMGB1 to monocyte cultures activates the production of TNF-α， IL-1β， IL-6， and IL-8 but not IL-10 or IL-12. Surprisingly， HMGB1-induced TNF-α production is obviously delayed compared with LPS-induced TNF-α formation. HMGB1-induced TNF-α release is biphasic， with the first peak at 3 hours and the other after 8-10 hours. LPS-induced TNF-α production culminates after 2-hour stimulation and is virtually undetectable by 8 hours.[12] HMGB1 treatment of neutrophils has been testified to induce an activated phenotype as determined by gene expression profiling， including markedly enhanced expression of TNF-α， IL-1β and IL-8.[13] Human microvascular endothelial cells also react with up-regulation of adhesion molecules and formation of inflammatory cytokines upon HMGB1-indction.[14] Thus HMGB1 can lead to production of multiple proinflammatory mediators by a variety of cells， and importantly it might induce its own release from monocytes and macrophages. This indicates that HMGB1 plays a pivotal role in host proinflammatory reactions.

Inflammation-promoting activity of HMGB1 in various diseases

Accumulating data confirm the existence of extracellular/cytoplasmic HMGB1 in various inflammatory conditions. Concerning acute inflammation， HMGB1 is closely related to immune dysfunction in patients with sepsis， pneumonia and endotoxemia. The level of serum HMGB1 is significantly elevated 16-32 hours after systemic LPS challenge of mice， and it is lethal to systemic injection of recombinant HMGB1 to mice. This further supports the pathogenic role of HMGB1 in endotoxemia.[4] Reproduction of experimental sepsis in mice by cecal ligation and puncture （CLP） also significantly elevated the serum level of HMGB1.[6] The values of HMGB1 in sera collected from septic patients were higher than those from healthy volunteers.[4] Intra-tracheal instillation of HMGB1 to mice resulted in acute lung injury with accumulation of neutrophils， edema and accumulation of inflammatory mediators. The level of serum HMGB1 was also increased in patients suffering from hemorrhagic shock.[15] A model of burn injury showed increased HMGB1 mRNA levels in the liver and lungs， similar to those of proinflammatory cytokine mRNA.[16] Additionally， hepatic HMGB1 mRNA expression elevated after exposure in two experimental models of hepatitis.[17] HMGB1 has recently been reported to have proinflammatory activity within the central nervous system， acting as an endogenous pyrogen. It is revealed that HMGB1 might play a potential pathogenic role in chronic inflammatory conditions. Furthermore， cytoplasmic and extracellular HMGB1 was present in experimental arthritis models as well as in human rheumatoid arthritis. HMGB1 was strictly localized to the nucleus of each cell in normal synovial tissue， whereas cytoplasmic localization of HMGB1 as well as extracellular depositions were abundant in arthritic synovial tissue. HMGB1 could be detected in a majority of investigated synovial fluid samples from patients with rheumatoid arthritis.[18] In muscle biopsies from patients with chronic myositis， HMGB1 could be detected cytoplasmically in muscle fibers， in inflammatory infiltrates and in small vessel endothelial cells. Therefore， the essential role of HMGB1 in inflammatory conditions indeed seems to be substantiated in an in vivo setting in both mouse and humans. Thus HMGB1 serves as a potential target molecule for therapeutic intervention. Nevertheless， it is drastic to explore the precise mechanism of HMGB1 in the induction of inflammatory response and immune dysfunction before HMGB1-tageted therapy administrated in treatment of sepsis through converting the inflammatory/immunologic derangement following acute insults.

HMGB1 in the development of immune dysfunction

after acute insults

The initiation and control of an adaptive immune response is critical for health and disease， and dendritic cells （DCs） are essential to these processes.[19] DCs detect evolutionarily conserved molecular structures unique to foreign pathogens， such as LPS， and DNA molecules containing unmethylated CpG motifs. They also respond to endogenous signals of cellular distress or damage.[20] Interaction with these agents stimulates DCs to undergo the process of maturation. Endogenous signals that cause DCs to mature are an important class of stimuli that might contribute to the initiation or perpetuation of an immune response against pathogens. In contrast， if these factors are released chronically and/or in the absence of infection， they could potentially contribute to the activation of self-reactive T cells and play a role in the development of autoimmunity.[20]

Wakkach et al[21] found that there was a distinct subset of tolerogenic DCs characterized by the stable phenotype CD11clowCD45RBhigh. These regulatory DCs can be derived from bone marrow cells in the presence of granulocyte-macrophage colony stimulating factor， TNF-α as well as IL-10， and it secretes high levels of IL-10 following activation， and induces T-regulator type 1 cells both in vivo and in vitro.[22，23] Recently we reported that as a subset of naturally existing DCs， CD11clowCD45RBhigh DCs were presented in the spleen and could protect mice from acute severe inflammatory response secondary to thermal injury.[24] Therefore， it is critical to investigate the mechanism underlying IL-10-producing CD11clowCD45RBhigh DCs （the other counterpart comparing to IL-12 producing CD11chighCD45RBlow DCs）-mediated regulation of host inflammation and immunity under pathophysiological conditions. Using both HMGB1-treated CD11chighCD45RBlow DCs and CD11clowCD45RBhigh DCs and coculturing them with CD4+ T cells stimulated by CD3， we found in a study in vitro that CD11clowCD45RBhigh DCs might be the major source of IL-10， which is an anti-inflammatory cytokine that plays an important role in modulating the host immune response and can direct T cells to differentiate into Th2. Taken together， HMGB1 induces the excessive differentiation of IL-10-producing CD11clowCD45RBhigh DCs， thereby mediating suppression of T lymphocyte.

In another study in vivo， the results showed that expression levels of CD152 （cytotoxic T-lymphocyte-associated antigen 4， CTLA-4） and forkhead/winged helix transcription factor p3 （Foxp3） were strongly up-regulated on splenic regulatory T cells （Tregs） during postburn days 1-7 in comparison to Tregs from sham-injured rats.[25] In order to verify whether the activation of Tregs was associated with excessive formation of HMGB1 after burn injury， EP was used to inhibit the effect of HMGB1in this study. It was found that treatment with EP could dramatically decrease the expression of CD152， Foxp3 on Tregs and IL-10 production after major burns. However， T cell proliferative activity and expression levels of IL-2 and IL-2Rα were markedly restored， and T cells were shifted to Th1. These data suggested that excessive release of HMGB1 might stimulate splenic Tregs to maturation， and further mediate suppression of immune function of T lymphocytes.[25]

HMGB1-targeted therapies in inflammatory conditions

With the discovery of HMGB1 as a potent mediator of inflammation and the presence of extranuclear HMGB1 in several inflammatory conditions， possible beneficial effects of HMGB1-targeted therapies have been investigated. It is hypothesized that the antibodies prevent LPS-induced lethality even when a delayed treatment regimen is prescribed. Treatment with HMGB1-specific polyclonal antibodies can significantly improve the outcome of LPS-induced acute lung injury. It is of great clinical significance that in experimental sepsis caused by CLP， HMGB1-targeted treatment has a much broader therapeutic window than other cytokine-targeted therapies previously investigated. Polyclonal anti-HMGB1 antibodies could be administered up to 24 hours following CLP with persistent efficacy，[26] whereas previous attempts with similar interventions with anti-TNF-α or anti-macrophage migration inhibitory factor antibodies have a much shorter therapeutic window. As septic patients are only admitted to hospital when sepsis is fully developed， these novel experimental results are encouraging for future clinical trials. The promising results with polyclonal anti-HMGB1 antibodies also initiated the development of other HMGB1 antagonists. To date two different HMGB1 antagonists， namely HMGB1 A-box protein and EP， have been successfully tested in experimental systems. Purified A-box protein has a clear potential for further clinical testing. EP， a stable lipophilic pyruvate derivative， has been demonstrated in vitro to inhibit the release of TNF-α and HMGB1 from LPS-stimulated macrophage cell lines. EP addition inhibited NF-κB translocation and p38 mitogen-activated protein kinase （MAPK） signaling， but the exact mechanism which inhibits HMGB1 release is not understood. Treatment with EP in the CLP-induced sepsis animal model was demonstrated to reduce lethality， even it was given as late as 24 hours after initiation of peritonitis. Treatment with EP also decreased the systemic levels of HMGB1 in these animals.[11，27] Moreover， administration of EP could markedly inhibit HMGB1 release and improve the splenocyte proliferative response in thermally injured rats.[25]

New concept of HMGB1-targeted Chinese herbal therapies in sepsis

With the development of traditional Chinese medicine in recent years， it has been proven that traditional Chinese herbal materials and their extracts have remarkable effective in treating severe sepsis. In traditional Chinese medicine， herbs have been used as immunostimulants for thousands of years.[28] These herbs contain many types of active components like polysaccharides， alkaloids or flavonoids. The immunostimulatory activities of herbal components have been widely studied in mice， chickens or cell lines，[29] and in some herbs （e.g）， Astragalus membranaceus or Nelumbo nucifera） their molecular mechanisms of action are well understood.[30] There is a growing interest in using medicinal herbs as immunostimulants in aquaculture.

Astragalus polysaccharides （APS） isolated from one of the Chinese herbs， Astragalus mongholicus （Huangqi）， are known to have a variety of immunomodulatory activities. We found that APS could induce the differentiation of splenic DCs from IL-12-producing CD11chighCD45RBlow DCs， and further induce activation of immune function of T lymphocytes with shifting of Th2 to Th1 in vitro. In addition， the effect of APS on T cell differentiation to Th1 was not associated with the inhibition of IL-10 production in CD11clowCD45RBhigh DCs. Obviously， the immune function of APS is absolutely controversy to HMGB1 in terms of the differentiation of DCs. Thus， APS， as the HMGB1-targeted Chinese herbal immune-regulator， might be of significance in converting the immune dysfunction associated with HMGB1 formation.

Another Chinese medicinal herb， Dang Gui （also known as "Dong Quai"， or Radix Angelicae Sinensis）]， has been used alone or in combination with others in the treatment of various inflammatory diseases.[31] Its medical use was first recorded in Shen Nong Ben Cao Jing， a medical classic； it was listed in the 22nd edition of the United States Dispensatory. Radix Angelicae Sinensis is often referred to as ginseng for females， and has been traditionally used to treat gynecological disorders such as abnormal， painful menstruation， pelvic pain， or uterine bleeding. A combination therapy with soy isoflavones （60 mg）， Angelica sinensis （100 mg）， and black cohosh （50 mg） was found to be efficacious in reducing the frequency and severity of menstrual migraines after one month of therapy.[32]

Recently， a number of preclinical studies have shown the beneficial effects of Angelica sinensis in animal models of bacteria-induced pneumonia， carrageenan-induced edema， and ethanol-induced hemorrhagic tissue damage.[33] It has been demonstrated that a low molecular weight fraction of Radix Angelicae Sinensis extract dose dependently demolished LPS-induced HMGB1 release in macrophage cultures. Angelica sinensis extract inhibited HMGB1 release in part by interfering with its cytoplasmic translocation， thereby preserving its nuclear localization in LPS-stimulated cells. In an animal model of lethal endotoxemia， repeated administration of herbal extract beginning 30 minutes before the onset of endotoxemia， significantly decreased circulating HMGB1 levels， and increased animal survival rate from 30% to 90%. These data suggest that Angelica sinensis extract protects against lethal endotoxemia in part through attenuating systemic release of HMGB1. Thus， more clinically relevant animal models should be established to explore the mechanisms of herbal extracts for the treatment of sepsis.

Danshen （Radix Salviae miltiorrhizae） is a medicinal herb （termed Shen） containing substance of premier medicinal value （termed Dan， cinnabar）， and has been widely used in China for patients with cardiovascular disorders.[34] Its beneficial effects are attributable to several red pigments including tanshinones I， II， IV， and cryptotanshinone， which exhibit various anti-inflammatory properties.[35，36] This medicinal herb contains substances such as tanshinone I， tanshinone IIA， and cryptotanshinone， which effectively down-regulated LPS-induced HMGB1 expression in macrophage/monocyte cultures. The delayed administration of tanshinone IIA-SS significantly attenuated systemic HMGB1 accumulation， indicating that tanshinone IIA-SS rescues mice from lethal sepsis partly through attenuation of systemic accumulation of late-acting mediators.

It has been reported that treatment with Xuebijing injection made of traditional Chinese herbs can markedly prevent the development of sepsis and ameliorate multiple organ damage in experimental and clinical settings， while the precise mechanism of its action remains to be elucidated. To address this issue， a study was performed to investigate the effect of Xuebijing injection on tissue HMGB1 expression and multiple organ dysfunction in rats with delayed resuscitation for burn shock. The results showed that both mRNA and protein expressions of HMGB1 were significantly enhanced in the lungs， liver， and kidneys 8-72 hours after scald injury compared to sham scald controls. Treatment with Xuebijing injection could significantly down-regulate tissue HMGB1 mRNA and protein expressions， and lower the functional values of multiple organs following injury.[37]

CONCLUSION

The immunopathogenesis of lethal sepsis remains obscure， but it is associated with dysregulated inflammatory response， tissue injury， and multiple organ dysfunction. The inflammatory response is mediated in part by bacterial LPS， which stimulates macrophages/monocytes to sequentially release early （e.g.， TNF-α and IL-1） and late （e.g.， HMGB1） mediators. Although early cytokines may be protective against infection， dysregulated inflammatory response sustained by late-acting mediators including HMGB1 may contribute to the development of tissue injury and organ dysfunction at the late stage of severe sepsis. Therefore， agents capable of selectively attenuating systemic HMGB1 accumulation may be potentially effective in the treatment of lethal sepsis. With the continuous research into the role of immunopathogenesis of HMGB1 in sepsis， it might be beneficial in future studies to explore the therapeutic potential of Chinese herbal medicine in the clinical management of human sepsis.[37] Almost surely， research into the immunomodulatory properties and mechanisms of action of herbal medicines will provide new insights into immune function and possible avenues of sepsis immunotherapy.

Funding： This study was supported in part by grants from the National Natural Science Foundation of China （30872683） and the National Basic Research Program of China （2005CB522602）..

Ethical approval： Not needed.

Conflicts of interest： No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

Contributors： Liu QY wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts.

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Received February 11， 2010

Accepted after revision May 27， 2010