[Frontiers in Bioscience S2, 1081-1091, June 1, 2010]
Targeting HMGB1/TLR4 signaling as a novel approach to treatment of cerebral ischemia
Qing-Wu Yang, Jing Xiang, Yu Zhou, Qi Zhong, Jing-Cheng Li
Department of Neurology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China
TABLE OF CONTENTS
1. ABSTRACT
HMGB1 is a ubiquitous, highly conserved DNA-binding protein with well-established functions in the maintenance of nuclear homeostasis. Much of the recent work about its signaling functions in the brain has focused on its proinflammatory properties and relationship to known inflammatory receptors such as toll-like receptor 4 (TLR4). HMGB1 is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain, indicating that HMGB1 acts as a novel mediator in cerebral ischemic injury. Consistently, numerous reports point to TLR4 as a pivotal player in the ischemic brain. The use of HMGB1 and TLR4 ligand as preconditioning stimulus may be benefit of the outcome of cerebral ischemia. Therefore, this review presents the latest findings supporting the involvement of HMGB1 and TLR4 in cerebral ischemia. Targeting HMGB1/TLR4 signaling may provide a novel therapeutic approach for clinical prevention of cerebral ischemic injury.
2. INTRODUCTION
Stroke is the second most common cause of death worldwide. Despite extensive efforts, thrombolytic medications, like tissue plasminogen activator (tPA), remain the only available intervention proven to enhance functional recovery in humans once a stroke has occurred. Thrombolysis is safe and effective only within 3 hours of the onset of symptoms. This short time window results in a low treatment rate and safer treatment regimes that can be used over a wider time window are desperately needed. After stroke, pathology may spread as toxic factors from the core of the lesion pose a risk for cells in the penumbra. One such factor is cortical spreading depression, which has been shown to promote the enlargement of ischemic lesions (1). In addition, soluble mediators from the necrotic core area may diffuse to the adjacent tissue and elicit a delayed inflammatory response that contributes to neuronal cell death. Recent reports provide evidence that high mobility group box 1 (HMGB1) and its receptor, the toll-like receptor-4 (TLR4), are pivotal mediators of cerebral ischemic inflammation and injury (2-9).
HMGB1 (also known as amphoterin) is a non-histone DNA-binding protein with high electrophoretic mobility (10, 11). HMGB1 participates in nucleosome formation and regulation of gene transcription (12). The protein binds to the minor groove of duplex DNA and induces conformational changes in chromatin architecture, thereby facilitating supramolecular nucleoprotein complex assembly and transcription factor recruitment (10, 12). In addition to its role in the regulation of nuclear homeostasis, HMGB1 has extracellular signaling functions through interactions with different receptors such as the receptor for advanced glycation end products (RAGE), TLR2, and TLR4 (13-18). Specifically, nuclear HMGB1 can be released into the extracellular space either passively from cells undergoing necrosis or actively from numerous cell types (19). When present in the extracellular milieu, it can activate the innate system and mediate a wide range of physiological and pathological responses (20).
Several studies highlight the role of HMGB1 in cerebral ischemic injury (5-9).HMGB-1 is released from neurons soon after ischemic injury and that it subsequently induces neuroinflammation in the post-ischemic brain (7, 9). For example, HMGB1 down-regulation mediated by short hairpin RNA (shRNA) reduces the severity of lesions in a stroke model (7). Notably, intravenous injection of anti-HMGB1 monoclonal antibody also causes a dramatic reduction in infarct size in stroke model (21, 22). Taken together, these findings indicate that HMGB1 is a proinflammatory cytokine-like factor that contributes to delayed inflammatory processes in the post-ischemic brain. However, how the receptors involved in HMGB1 signaling are activated and the relative contributions of the downstream molecules are still not understood.
TLR4 mediates many of the extracellular functions of HMGB1(14, 16, 23, 24). TLR4 is a signaling receptor known to activate the innate immune system in response to systemic bacterial infection and cerebral injury (25). Recently, TLR4 was shown to play a key role in ischemic brain injury (2-4). Notably, TLR4-deficient mice have smaller cerebral infarctions and a lower level inflammatory response after an experimental stroke, suggesting that TLR4 signaling is involved in brain damage (3). Interestingly, endogenous mediators that have been isolated after brain ischemia have been identified as ligands of TLR4, including HMGB1(26). This indicates that TLR4 may interact with HMGB1 and contribute to neuronal injury in cerebral ischemic brain. This review therefore summarizes the recent advances on the role of HMGB1 in the brain, the putative HMGB1/TLR4 signaling pathways, and the role of HMGB1/TLR4 in cerebral ischemic injury. Finally, the therapeutic potential of inhibitors of HMGB1/TLR4 signaling in the treatment of cerebral ischemia is discussed.
3. THE ROLE OF HMGB1 IN THE BRAIN
HMGB1 secretion is not fully understood. Under normal conditions, HMGB1 is localized in the cell nucleus and diffusely distributed in the cell cytoplasm (27). In the nucleus, it binds to DNA (19). Nuclear translocation of HMGB1 is controlled by nuclear localization signal sequences NLS and NLS2 (28). During challenge, HMGB1 becomes acetylated on lysine residues within the nuclear localization signals. Once hyper-acetylated, the NLS is masked and HMGB1 nuclear import is prevented, thereby leading to the cytoplasmic accumulation of the protein. The hyper-acetylated HMGB1 then appears to be loaded into secretory lysosomes; the ultrastructural features of HMGB1-containing organelles suggest that they are secretory lysosomes (28, 29). The fusion of these secretory lysosomes with the plasma membrane liberates HMGB1 into the extracellular environment (30).
HMGB1 has been characterized as a proinflammatory cytokine (15,31). It is secreted by activated macrophages, natural killer cells, and myeloid dendritic cells in response to inflammatory stimuli (15,28,32,33). Recently, several studies have highlighted the proinflammatory characteristics of HMGB1 in the central nervous system (CNS). Intracerebrocentricular administration of HMGB1 increases levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 in brain and induces fever, anorexia, taste aversion, and weight loss in mice (34, 35). In fact, HMGB1 is found in the nuclei of neurons, astrocytes, and pituicytes in the brain (5, 9, 36). Neurons are one of the principal sources of HMGB-1 release during ischemic injury (9).Studies on rodent brain development suggest that HMGB1 regulates neuronal migration and sprouting (37). In the developing rat brain, HMGB1 localizes to the advancing plasma membrane of filopodia at the leading edges in motile cells, which in turn promotes the outgrowth of neuritis (38, 39). HMGB1 is differentially expressed in the mouse brain at various steps of development and tends to be down-regulated in the adult animal (40). These results taken together, point to an important role of HMGB1 in CNS function.
HMGB1 is found in the nuclei of neurons, astrocytes, and pituicytes in the brain (5, 9, 36). Neurons are one of the principal sources of HMGB-1 release during ischemic injury (9). Studies on rodent brain development suggest that HMGB1 regulates neuronal migration and sprouting (37). In the developing rat brain, HMGB1 localizes to the advancing plasma membrane of filopodia at the leading edges in motile cells, which in turn promotes the outgrowth of neuritis (38, 39). HMGB1 is differentially expressed in the mouse brain at various steps of development and tends to be down-regulated in the adult animal (40).These results taken together, point to an important role of HMGB1 in normal CNS function. HMGB1 has been characterized as a proinflammatory cytokine (15, 31) .It is secreted by activated macrophages, natural killer cells, and myeloid dendritic cells in response to inflammatory stimuli (15,28,32,33) . Recently, several studies have highlighted the proinflammatory characteristics of HMGB1 in the central nervous system (CNS). Intracerebrocentricular administration of HMGB1 increases levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 in brain and induces fever, anorexia, taste aversion, and weight loss in mice (34, 35).
HMGB1 secretion is not fully understood. Under normal conditions, HMGB1 is localized in the cell nucleus and diffusely distributed in the cell cytoplasm (27) .In the nucleus, it binds to DNA (19). Nuclear translocation of HMGB1 is controlled by nuclear localization signal sequences NLS and NLS2 (28). During challenge, HMGB1 becomes acetylated on lysine residues within the nuclear localization signals. Once hyper-acetylated, the NLS is masked and HMGB1 nuclear import is prevented, thereby leading to the cytoplasmic accumulation of the protein. The hyper-acetylated HMGB1 then appears to be loaded into secretory lysosomes; the ultrastructural features of HMGB1-containing organelles suggest that they are secretory lysosomes (28, 29). The fusion of these secretory lysosomes with the plasma membrane liberates HMGB1 into the extracellular environment (30).
4. TLR4 AS A KEY RECEPTOR FOR HMGB1 IN THE BRAIN
HMGB1 appears to signal through multiple receptors such as RAGE, TLR2 and TLR4, and presumably other unknown receptors (41). TLR4 mediates many of the extracellular functions of HMGB1 (14, 16, 23, 24). The extent of TLR4 expression in brain cells has been controversial. A number of studies have demonstrated that TLR4 is mainly expressed on glial cell populations, including microglia, astrocytes, and oligodendrocytes, but not on neurons (42-44). However, several findings suggest that neurons may express at least some TLRs responsive to viral RNA or bacterial proteins (45, 46). During the past four years, evidence for the neuronal expression of TLRs has increased, suggesting a role for this receptor family in neurons during physiological as well as pathological conditions (47, 48). Furthermore, recent expression studies confirm that cerebral ischemia results in the up-regulation of mRNAs for TLR2, TLR4, and TLR9 in the mouse neurons (47-49). Notably, microglial cells expresses all known TLRs. In fact, microglia have been reported to express mRNAs for TLRs 1 through 9, whereas neurons and oligodendrocytes express only mRNA for TLR3 (50,51,52). However, further confirmation using single-cell polymerase chain reaction will be required to exclude contaminating microglia as a source of TLR mRNA. Furthermore, the expression of TLR4 at the protein level remains to be investigated in the brain cells.
TLR4 predominantly recognizes lipopolysaccharide (LPS) from Gram-negative bacteria (53). A number of endogenous proteins, including HMGB1, heat shock proteins 60 and 70, oxidized low-density lipoprotein, surfactant protein A, fibronectin, and defensin, bind to and stimulate TLR4 (54). However, the only molecule known to stimulate TLR4 signaling that has been definitively shown to be involved in ischemic injury is HMGB1 (55). HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Importantly, optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes requires intact TLR4 signaling (55). Thus, TLR4 participates not only in the recognition of HMGB1 but also in its release through a mechanism involving ROS production, providing a mechanism by which ischemic tissues notify the immune system of the potential loss of tissue integrity. To date, it is not known whether HMGB1 involvement in cerebral ischemic injury is dependent on TLR4 signaling, however, the interaction of TLR4 and HMGB1 seems certain in the cerebral ischemic process. One of our ongoing studies has demonstrated that the release of HMGB1 by necrotic neurons which triggers the activation of microglia is TLR4 dependent (unpublished data). Moreover, in a mouse model of cerebral ischemia/reperfusion (I/R) injury, TLR4-deficient mice have a lower inflammatory response and less extensive I/R injury after administration with HMGB1 that untreated mice (unpublished data). Further, a recent study showed that RAGE mediates ischemic brain injury induced by HMGB1 (8). These results taken together, point to a key role of HMGB1 in triggering inflammation and injury following brain ischemia.
5. HMGB1/TLR4 SIGNALING PATHWAYS
HMGB1/
MyD88 and Toll/IL-1 receptor-domain containing adaptor protein (TIRAP) are associated with TLR4 after receptor activation by HMGB1(16,57). MyD88 recruits members of the IRAK family which activate the downstream TRAF6 kinase. Dominant negative (dn) MyD88, dnTIRAP, dnIRAK1, and dnIRAK2 inhibit HMGB1-induced NF-κB reporter gene activity, suggesting that these proteins are key players in the TLR4 signaling cascade (16). IRAK1 activates TRAF6, which results in the formation of a complex with transforming growth factor b (TGF-b ) activated kinase 1 (TAK1) and TAK1 binding protein 2 (TAB2). However, though expression of dnTRAF6 clearly inhibits the NF-κB reporter gene expression after stimulation of HMGB1, neither the expression of dnTAB2 nor dnTAK1 inhibit NF-κB activation stimulated by HMGB1. Thus, TAB2 and TAK1 are not important in HMGB1 signaling through TLR4 (16).
TLR4 signaling may be either MyD88 dependent or independent (Fig1) (58). Nevertheless, the most prominent effect of TLR activation is the induction of NF-κB-dependent gene expression. The NF-κB family of transcription factors contains five members that function as hetero- or homodimers. The dimers are sequestered in the cytoplasm in an inactive form by inhibitor of NF-κB (IκB). NF-κB is translocated to the nucleus when IκB is phosphorylated and subsequently degraded. The IκB kinase (IKK) complex, consisting of IKKa , IKKb , and IKKg , is the main activator of NF-κB and is itself activated by diverse upstream signals (Fig1) (59).
How activation of TLR4 mediates the phenotypic effects of HMGB1 is still unclear. HMGB1 may directly interact with TLR4, causing cell activation and the NF-κB-dependent transcription of proinflammatory cytokines (14). HMGB1 also binds to cytokines, in particular IL-1b (60). HMGB1 also catalytically disaggregates LPS and transfers it to soluble CD14 and to leukocytes (61). This enhanced access sustains a positive feedback amplificatory loop, facilitating TLR4-mediated inflammatory responses (61). Interestingly, in a recent study, we observed cerebral I/R injury in MyD88 knockout mice (4). Compared with wild-type mice, 6 hours of cerebral ischemia followed by 24 hours of reperfusion did not significantly change the cerebral infarction area and neurologic impairment scores in MyD88 knockout mice, suggesting that TLR4 may contribute to cerebral I/R injury through an MyD88-independent signal pathway (4). Moreover, a most recent study indicates that the TIR domain-containing adaptor protein(TRIF)-dependent signaling pathway is not required for cerebral I/R injury in mice (62).Therefore, TLR4-mediated cerebral ischemia injury may be either MyD88 or TRIF independent.
6. ROLE OF HMGB1 IN CEREBRAL ISCHEMIA
Very recently, HMGB1 has been implicated in the mechanism of ischemic brain damage (5-9, 21, 63). In patients with ischemic stroke, the serum or plasma levels of HMGB1 are dramatically higher than those in controls (8, 63). In an animal model of ischemic stroke, the serum levels of HMGB1 are increased 4 hours after ischemia and HMGB1 is released into the extracellular space immediately after ischemic insult where it subsequently induces the release of inflammatory mediators in the post-ischemic brain (6, 7). The relocation dynamics of HMGB1 in the neuronal cells are intriguing: HMGB1 is initially expressed in the nucleus of neurons and astrocytes of the mouse brain. It predominantly translocates into the cytoplasm of neurons within the ischemic brain and then rapidly disappears from neurons (5,6,7,9). HMGB1 is translocated from neuronal nuclei to the cytoplasm and subsequently depleted from neurons 1 hour after middle cerebral artery occlusion (MCAO) (6,9). These data indicate that HMGB1 is an early inflammatory mediator that contributes to the initial stages of the inflammatory response in the ischemic brain.
HMGB1 proinflammatory signaling appears to begin in the first hour after focal ischemia and may continue for 24 hours thereafter (5). HMGB1 is localized in soma and processes of ischemic neurons but levels are rapidly (after 1-3 hours) reduced in ischemic brain tissue and remain inhibited up to 24 hour after ischemia (5). These findings, together with the evidence that HMGB1 levels increase in the cerebrospinal fluid and serum after brain ischemia in the rat, suggest that the protein translocates from the nuclei of ischemic neurons to the extracellular space and then to the liquor (7). Importantly, this may provide a wide window for therapeutic intervention when HMGB1 is targeted.
Indeed, down-regulation of HMGB1 in brain using shRNA correlates with diminished infarct volumes in the rat (7). Inhibition of HMGB1 expression by shRNA reduced ischemia-dependent microglia activation and induced TNF-α and IL-1b expression in the ischemic brain (7). Moreover, HMGB1 promotes microglia activation (5,7). Therefore, evidence that inflammation plays an active role of in the pathogenesis of ischemic brain injury, along with the cytokine functions of HMGB1 suggest that the detrimental effect of the protein during brain ischemia is due, at least in part, to its capability to promote neuroinflammation.
7. ROLE OF TLR4 IN CEREBRAL ISCHEMIA
TLR4 plays a key role in the innate immunity of the CNS (43). Numerous studies demonstrate that TLR4 participates in cerebral injury upon ischemic stroke. Several expression studies confirm that cerebral ischemia results in the up-regulation of TLR4 mRNA in neurons as early as 1 hour after initiation of ischemia in vivo (4, 47). Importantly, cortical neuronal cultures from TLR4-deficient mice show increased survival after glucose deprivation (47). Mice lacking TLR4 exhibit reduced infarct size compared with wild-type mice after cerebral ischemia injury (2, 3, 47, 64, 65). TLR4 mutant mice subjected to MCAO or animals suffering global cerebral ischemia exhibit improved neurological behavior and reduced edema, as well as reduced levels of secretion of proinflammatory cytokines such as TNF-a and IL-6 (2, 3, 65). In addition, mice lacking TLR4 have reduced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), and interferon g (3, 65). Likewise, a TLR4 mutation confers protection against MCAO (64). Moreover, after MCAO, loss of TLR4 function is associated with reduced expression of p38 and Erk1/2 in damaged neurons, implicating TLR4 in MCAO injury (2, 3, 47, 64). Taken together, these studies indicate that TLR4 signaling modulates the severity of ischemia-induced neuronal damage and suggests TLR4 should be a target of stroke therapy.
Interestingly, several lines of evidence suggest that TLR4 might also be involved in the preconditioning-induced protective effect against ischemic brain injury (66, 67). First, TLR4 signaling activates nuclear NF-κB and induces expression of mediators such as iNOS and COX-2, which participate in ischemic tolerance (68). Second, preconditioning with LPS, a TLR4 ligand, produces ischemic tolerance through a TNF-a -dependent process (69). TLR4-mediated activation of NF-κB leads to the expression of TNF-a , iNOS, and COX-2 and induces neuroprotective effects (66). Therefore, as ischemic preconditioning activates endogenous signaling pathways that culminate in marked protection against ischemic brain damage, drugs that stimulate TLR4 might protect against cerebral ischemic injury.
However, several basic questions still need to be answered before the involvement of TLR4 in cerebral ischemia injury is completely clarified. Thus far, studies on TLRs in ischemic brain stroke have mainly focused on ischemic damage in TLR4 mutant mice and, to a lesser extent, TLR2 mutant mice. Although this approach has provided some understanding of the relevance of TLR signaling in ischemic brains, it has not enabled an understanding of the role of TLR signaling in specific cell types. This issue is of high importance because of the involvement of many different cells in the pathology of ischemic brain injury, including for example, neurons, astrocytes, microglial, endothelial cells, and invading immune cells.
8. HMGB1/TLR4-TARGETED THERAPIES IN CEREBRAL ISCHEMIA
HMGB1 has been demonstrated to be a significant contributor to ischemia injury through a TLR4-dependent mechanism (55). Importantly, although HMGB-1 clearly contributes to the early stages of inflammation in brain ischemia, it may also contribute to later stages of inflammation by activating microglia (7). Therefore, HMGB-1 may exert multiple proinflammatory effects in the ischemic brain, which means that the time frame for clinical intervention against cerebral ischemic injury would be extended relative to the 3-hour window for thrombolytic therapy. Similarly, the use of TLR4 ligands as ischemic prophylactic therapy provides a powerful new paradigm that should be explored for stroke therapy (Fig 2 and table.1).
8.1. HMGB1 as a target of therapy in cerebral ischemia
HMGB1 has proven to be an excellent therapeutic target in experimental models of infectious and inflammatory disorders, including sepsis, trauma, cancer, and rheumatoid arthritis (70-72). The concept of counteracting HMGB1 in the context of cerebral ischemic injury has so far been explored with strategies based on HMGB1 neutralization, inhibition of HMGB1 synthesis, and prevention of extracellular HMGB1 release. Therapeutic agents to treat cerebral ischemia may include anti-HMGB1 antibodies, HMGB1 A box protein, and HMGB1 preconditioning.
The HMGB1 mAb that has been evaluated in a rat ischemic model is directed to the end of the repetitive C-terminal tail of HMGB1 (21). Mori et al. reported that treatment with HMGB1 mAb remarkably ameliorated brain infarction in rats, even when the mAb was administered after the start of reperfusion (22). Furthermore, the accompanying neurological deficits in locomotor function were significantly improved (22). Additionally, some biochemical markers such as the expression of TNF-α, iNOS and matrix metalloproteinase-9 were altered by mAb injection (22). Similarly, intervention with neutralizing polyclonal anti-HMGB1 antibodies can prevent the progression of disease due to established stoke in rodents (8). Neutralizing strategies are reported to specifically inhibit extracellular HMGB1 activity rather than prevent its secretion, therefore, current efforts are focused on developing anti-inflammatory strategies that inhibit HMGB1 secretion (32).
HMGB1 box A is a functional antagonist of the proinflammatory effects mediated by full-length HMGB1 protein through competitive bind to RAGE (73). HMGB1 box A has been used as a pharmacological tool to inhibit the effects of HMGB1 that are mediated through RAGE (73, 74). HMGB1 box A protein therapy confers significant clinical protection in experimental inflammatory conditions, including lethal endotoxemia and arthritis (73, 75). In a study of stroke, systemic administration of HMGB1 box A protein significantly ameliorated ischemic brain injury (8). Thus, there may be therapeutic potential in using genetically engineered peptides to decrease inflammation.
Recently, the use of HMGB1 as a preconditioning stimulus has been explored (76). Exogenous HMGB1, given as a pharmacologic pretreatment, has been shown to protect against hepatic ischemia injury (77). Mice were pretreated with a single HMGB1 injection ranging from 2 to 20 m g, administered systemically 1 hour prior to ischemia of the liver. Protection was demonstrated by decreased levels of circulating alanine transaminase. In addition, levels of circulating TNF-a and IL-6 were also decreased (77). The study using HMGB1 as a preconditioning agent also investigated the role of TLR4 in preconditioning (77).The pretreatment with HMGB1 did not confer any additional protection in TLR4 mutant mice compared to wild-type mice (77). Therefore, the mechanism of HMGB1 preconditioning is a TLR4-dependent phenomenon. Taken these together indicate HMGB1 preconditioning can be protective in ischemia. However, to date, the use of HMGB1 as a preconditioning pharmacologic treatment in cerebral ischemic injury has not been explored.
8.2. TLR4 as a target of therapy in cerebral ischemia
A number of studies have demonstrated that TLR4 is expressed on all brain cells, including microglia, astrocytes, oligodendrocytes, and neurons (42-44, 47, 48). In cerebral ischemia, TLR4 is significantly up-regulated and may modulate the severity of neuronal damage, suggesting TLR4 may be a target of stroke therapy (48). Our previous study demonstrated that systematic administration of TLR-4 mAb remarkably ameliorated cerebral infarction and edema in cerebral I/R mice. Moreover, treatment with TLR-4 mAb significantly improved the neurological deficits and the expressions of inflammatory mediators as TNF-α, IL-6, IL-1 and MMP-9 were dramatically reduced (78).
TLR4-induced tolerance to cerebral ischemia was first demonstrated with low dose systemic administration of LPS, which causes spontaneously hypertensive rats to become tolerant to subsequent ischemic brain damage induced by MCAO (79). Since then, LPS-induced tolerance to brain ischemia has been demonstrated in mouse models of stroke (66,69, 80).Neuroprotection induced by LPS is time and dose dependent. Tolerance appears by 24 hour after LPS administration and extends through 7 days but is gone by 14 days (69). Protective doses of LPS appear to depend on the model and the dose.(69, 81, 82). Tolerance induction has been shown to require new protein synthesis and a modest inflammatory response (83). Specifically, TNF-a has been implicated as a mediator of LPS-induced ischemic tolerance because inhibition of TNF-a systemically or within the brain blocks neuroprotective effect and mice lacking TNF-a are not protected by LPS preconditioning (66,69,79). Therefore, the use of LPS preconditioning may prove beneficial in cerebral ischemic injury.
9. PERSPECTIVE AND CONCLUSIONS
Considering that the release of HMGB1 takes place early after the cerebral ischemia, new therapies, like neutralizing antibodies or drugs with antagonist characteristics, that inhibit HMGB1 signaling should produce a neuroprotective effect. Indeed, a recent study demonstrates that minocycline, a semisynthetic tetracycline antibiotic, attenuates both oxygen-glucose deprivation-induced HMGB1 release and HMGB1-induced cell death (84). Moreover, administration of minocycline for 14 days inhibits activated microglia expressing HMGB1 and decreases neurologic impairment induced by cerebral ischemia (85). Intriguingly, edaravone, a free radical scavenger clinically used for the treatment of cerebral infarction, was recently reported to rescue rats from cerebral infarction by attenuating the release of HMGB1 in neuronal cells (86). Another novel clinical medicine, cannabidiol, decreases both cerebral infarction and HMGB1 levels in the early ischemic phase (87).Together, these findings open new therapeutic possibilities for treatment of cerebral ischemic injury via an HMGB1-inhibiting mechanism.
A growing body of evidence points to a potential novel and pivotal role for HMGB-1 in the TLR4 signaling pathway that links the very early stage responses to cerebral ischemic injury with the activation of local neuroinflammatory responses. Likely, efficient inhibition of HMGB1/TLR-4 signaling will ameliorate inflammatory injury in cerebral ischemia. However, the complexity of inflammatory signaling in cerebral ischemic injury raises the question whether targeting HMGB-1 or TLR4 alone will be effective. Moreover, the mechanism by which HMGB1 exerts its proinflammatory cytokine-like effects in the cerebral ischemia is still unknown. Additionally, the therapeutic window of time during which treatments targeting HMGB-1 or TLR4 must be initiated has not yet been determined.
To summarize, HMGB1 and TLR4 play important roles in cerebral ischemic injury and in ischemic prophylaxis. Potential drugs candidates might target the HMGB1 signaling pathway at different levels in order to prevent HMGB1 release and inhibit HMGB1 binding to its receptors. HMGB1 preconditioning may also be a useful therapeutic strategy. The use of TLR4 ligands as ischemic prophylactic therapy also provides powerful new paradigm that should be explored for stroke therapy.
10. ACKNOWLEDGMENTS
Drs Qing-Wu Yang, Jing Xiang contributed equally to this work. This work was supported in part by a grant from the National Natural Science Foundation of China (No. C30870859), the Chongqing Natural Science Foundation (CSTC, 2008BB5279).
11. REFERENCES
1. T.Takano, G.F. Tian, W. Peng, N. Lou, D. Lovatt, A.J. Hansen, K.A. Kasischke and M. Nedergaard:Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci 10,754-762 (2007)
doi:10.1038/nn1902
PMid:17468748
2. C.X. Cao, Q.W. Yang, F.L. Lv, J. Cui, H.B. Fu, and J.Z. Wang: Reduced cerebral ischemia-reperfusion injury in toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 353,509-514 (2007)
doi:10.1016/j.bbrc.2006.12.057
PMid:17188246
3. J.R. Caso, J.M. Pradillo, O. Hurtado, P. Lorenzo, M.A. Moro and Lizasoain I: Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115, 1599-1608 (2007)
doi:10.1161/CIRCULATIONAHA.106.603431
PMid:17372179
4. Q.W. Yang, J.C. Li, F.L. Lu, A.Q. Wen, J.Xiang, L.L. Zhang, Z.Y. Huang and J.Z. Wang: Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. J Cereb Blood Flow Metab 28, 1588-1596 (2008)
doi:10.1038/jcbfm.2008.50
5. G. Faraco, S. Fossati, M.E. Bianchi, M. Patrone, M. Pedrazzi, B. Sparatore, F. Moroni and A. Chiarugi:High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem 103,590-603 (2007)
doi:10.1111/j.1471-4159.2007.04788.x
PMid:17666052
6. J.B. Kim, C.M. Lim, Y.M. Yu and J.K. Lee:Induction and subcellular localization of high-mobility group box-1 (hmgb1) in the postischemic rat brain. J Neurosci Res 86,1125-1131 (2008)
doi:10.1002/jnr.21555
PMid:17975839
7. J.B. Kim, J. Sig Choi, Y.M. Yu, K. Nam, C.S. Piao, S.W. Kim, M.H. Lee, P.L. Han, J.S. Park and J.K. Lee:Hmgb1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26, 6413-6421 (2006)
doi:10.1523/JNEUROSCI.3815-05.2006
PMid:16775128
8. S. Muhammad, W. Barakat, S. Stoyanov, S. Murikinati, H. Yang, K.J. Tracey, M. Bendszus, G. Rossetti, P.P. Nawroth, A. Bierhaus and M. Schwaninger: The hmgb1 receptor rage mediates ischemic brain damage. J Neurosci 28,12023-12031 (2008)
doi:10.1523/JNEUROSCI.2435-08.2008
PMid:19005067
9. J. Qiu, M. Nishimura, Y. Wang, J.R. Sims, S. Qiu, S.I. Savitz, S. Salomone and M.A. Moskowitz:Early release of hmgb-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28,927-938 (2008)
doi:10.1038/sj.jcbfm.9600582
10. G.H. Goodwin, C. Sanders and E.W. Johns: A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem 38: 14-19 (1973)
doi:10.1111/j.1432-1033.1973.tb03026.x
PMid:4774120
11. J.O. Thomas:Hmg1 and 2: Architectural DNA-binding proteins. Biochem Soc Trans 29, 395-401 (2001)
doi:10.1042/BST0290395
PMid:11497996
12. M. Bustin:Revised nomenclature for high mobility group (hmg) chromosomal proteins. Trends Biochem Sci 26,152-153 (2001)
doi:10.1016/S0968-0004(00)01777-1
13. T. Haas, J. Metzger, F. Schmitz, A. Heit, T. Muller, E. Latz and H. Wagner:The DNA sugar backbone 2' deoxyribose determines toll-like receptor 9 activation. Immunity 28,315-323 (2008)
doi:10.1016/j.immuni.2008.01.013
PMid:18342006
14. M. Yu, H. Wang, A. Ding, D.T. Golenbock, E. Latz, C.J. Czura, M.J. Fenton, K.J. Tracey and H. Yang: Hmgb1 signals through toll-like receptor (tlr) 4 and tlr2. Shock 26,174-179 (2006)
doi:10.1097/01.shk.0000225404.51320.82
PMid:16878026
15. M.T. Lotze and K.J. Tracey: High-mobility group box 1 protein (hmgb1): Nuclear weapon in the immune arsenal. Nat Rev Immunol 5,331-342 (2005)
doi:10.1038/nri1594
PMid:15803152
16. J.S. Park, D. Svetkauskaite, Q. He, J.Y. Kim, D. Strassheim, A. Ishizaka and E. Abraham: Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279,7370-7377 (2004)
doi:10.1074/jbc.M306793200
PMid:14660645
17. M.E. Bianchi and A.A. Manfredi: High-mobility group box 1 (hmgb1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220,35-46 (2007)
doi:10.1111/j.1600-065X.2007.00574.x
PMid:17979838
18. H. Rauvala and A. Rouhiainen: Rage as a receptor of hmgb1 (amphoterin): Roles in health and disease. Curr Mol Med 7,725-734 (2007)
doi:10.2174/156652407783220750
PMid:18331230
19. M.E. Bianchi: Significant (re)location: How to use chromatin and/or abundant proteins as messages of life and death. Trends Cell Biol 14,287-293 (2004)
doi:10.1016/j.tcb.2004.04.004
PMid:15183185
20. S. Yamada and I. Maruyama: Hmgb1, a novel inflammatory cytokine. Clin Chim Acta 375,36-42 (2007)
doi:10.1016/j.cca.2006.07.019
PMid:16979611
21. K. Liu, S. Mori, H.K. Takahashi, Y. Tomono, H. Wake, T. Kanke, Y. Sato, N. Hiraga, N. Adachi, T. Yoshino and M. Nishibori: Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. Faseb J 21,3904-3916 (2007)
doi:10.1096/fj.07-8770com
PMid:17628015
22. S. Mori, K. Liu, H.K. Takahashi and M. Nishibori:Therapeutic effect of anti-nucleokine monoclonal antibody on ischemic brain infarction. Yakugaku Zasshi 129,25-31 (2009)
doi:10.1248/yakushi.129.25
PMid:19122433
23. M.A. van Zoelen, H. Yang, S. Florquin, J.C. Meijers, S. Akira, B. Arnold, P.P. Nawroth, A. Bierhaus, K.J. Tracey and T. Poll: Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products in high-mobility group box 1-induced inflammation in vivo. Shock 31,280-284 (2009)
doi:10.1097/SHK.0b013e318186262d
24. B. Kruger, S. Krick, N. Dhillon, S.M. Lerner, S. Ames, J.S. Bromberg, M. Lin, L. Walsh, J. Vella, M. Fischereder, B.K. Kramer, R.B. Colvin, P.S. Heeger, B.T. Murphy and B. Schroppel:Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci U S A 106,3390-3395 (2009)
doi:10.1073/pnas.0810169106
PMid:19218437 PMCid:2651292
25. M.D. Nguyen, J.P. Julien and S. Rivest: Innate immunity: The missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3,216-227 (2002)
doi:10.1038/nrn752
PMid:11994753
26. C. Zuany-Amorim, J. Hastewell and C. Walker: Toll-like receptors as potential therapeutic targets for multiple diseases. Nat Rev Drug Discov 1,797-807 (2002)
doi:10.1038/nrd914
PMid:12360257
27. M. Bustin and N.K. Neihart: Antibodies against chromosomal hmg proteins stain the cytoplasm of mammalian cells. Cell 16,181-189 (1979)
doi:10.1016/0092-8674(79)90199-5
28. T. Bonaldi, F. Talamo, P. Scaffidi, D. Ferrera, A. Porto, A. Bachi, A. Rubartelli, A. Agresti and M.E. Bianchi: Monocytic cells hyperacetylate chromatin protein hmgb1 to redirect it towards secretion. Embo J 22,5551-5560 (2003)
doi:10.1093/emboj/cdg516
PMid:14532127 PMCid:213771
29. S. Gardella, C. Andrei, D. Ferrera, L.V. Lotti, M.R. Torrisi, M.E. Bianchi and A. Rubartelli: The nuclear protein hmgb1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3,995-1001 (2002)
doi:10.1093/embo-reports/kvf198
PMid:12231511 PMCid:1307617
30. W. Parrish and L. Ulloa: High-mobility group box-1 isoforms as potential therapeutic targets in sepsis. Methods Mol Biol 361,145-162 (2007)
PMid:17172710
31. H. Yang, H. Wang, C.J. Czura and K.J. Tracey: The cytokine activity of hmgb1. J Leukoc Biol 78,1-8 (2005)
doi:10.1189/jlb.1104648
PMid:15734795
32. H. Wang, O. Bloom, M. Zhang, J.M. Vishnubhakat, M. Ombrellino, J. Che, A. Frazier, H. Yang, S. Ivanova, L. Borovikova, K.R. Manogue, E. Faist, E. Abraham, J. Andersson, U. Andersson, P.E. Molina, N.N. Abumrad, A. Sama and K.J. Tracey: Hmg-1 as a late mediator of endotoxin lethality in mice. Science 285,248-251 (1999)
doi:10.1126/science.285.5425.248
PMid:10398600
33. C. Semino, G. Angelini, A. Poggi and A. Rubartelli: Nk/idc interaction results in il-18 secretion by dcs at the synaptic cleft followed by nk cell activation and release of the dc maturation factor hmgb1. Blood 106,609-616 (2005)
doi:10.1182/blood-2004-10-3906
PMid:15802534
34. D. Agnello, H. Wang, H. Yang, K.J. Tracey and P. Ghezzi: Hmgb-1, a DNA-binding protein with cytokine activity, induces brain tnf and il-6 production, and mediates anorexia and taste aversion. Cytokine 18,231-236 (2002)
doi:10.1006/cyto.2002.0890
PMid:12126646
35. K.A. O'Connor, M.K. Hansen, C. Rachal Pugh, M.M. Deak, J.C. Biedenkapp, E.D. Milligan, J.D. Johnson, H. Wang, S.F. Maier, K.J. Tracey and L.R. Watkins: Further characterization of high mobility group box 1 (hmgb1) as a proinflammatory cytokine: Central nervous system effects. Cytokine 24,254-265 (2003)
doi:10.1016/j.cyto.2003.08.001
PMid:14609567
36. M. Passalacqua, M. Patrone, G.B. Picotti, M. Del Rio, B. Sparatore, E. Melloni and S. Pontremoli: Stimulated astrocytes release high-mobility group 1 protein, an inducer of lan-5 neuroblastoma cell differentiation. Neuroscience 82,1021-1028 (1998)
doi:10.1016/S0306-4522(97)00352-7
37. S. Fossati and A. Chiarugi: Relevance of high-mobility group protein box 1 to neurodegeneration. Int Rev Neurobiol 82,137-148 (2007)
doi:10.1016/S0074-7742(07)82007-1
38. H. Rauvala and R. Pihlaskari: Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons. J Biol Chem 262,16625-16635 (1987)
PMid:3680268
39. J. Merenmies, R. Pihlaskari, J. Laitinen, J. Wartiovaara and H.Rauvala: 30-kda heparin-binding protein of brain (amphoterin) involved in neurite outgrowth. Amino acid sequence and localization in the filopodia of the advancing plasma membrane. J Biol Chem 266,16722-16729 (1991)
PMid:1885601
40. S. Guazzi, A. Strangio, A.T. Franzi and M.E. Bianchi: Hmgb1, an architectural chromatin protein and extracellular signalling factor, has a spatially and temporally restricted expression pattern in mouse brain. Gene Expr Patterns 3,29-33 (2003)
doi:10.1016/S1567-133X(02)00093-5
41. Q.W. Yang, J.Z. Wang, J.C. Li, Y. Zhou, Q. Zhong, F.L. Lu, J. Xiang: High-mobility group protein box-1 and its relevance to cerebral ischemia. J Cereb Blood Flow Metab (2009)
42. C.C. Bowman, A. Rasley, S.L. Tranguch and I. Marriott: Cultured astrocytes express toll-like receptors for bacterial products. Glia 43,281-291 (2003)
doi:10.1002/glia.10256
PMid:12898707
43. S. Lehnardt, C. Lachance, S. Patrizi, S. Lefebvre, P.L. Follett, F.E. Jensen, P.A. Rosenberg, J.J. Volpe and T. Vartanian: The toll-like receptor tlr4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the cns. J Neurosci 22,2478-2486 (2002)
PMid:11923412
44. S. Lehnardt, L. Massillon, P. Follett, F.E. Jensen, R. Ratan, P.A. Rosenberg, J.J. Volpe and T. Vartanian:Activation of innate immunity in the cns triggers neurodegeneration through a toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100,8514-8519 (2003)
doi:10.1073/pnas.1432609100
PMid:12824464 PMCid:166260
45. M. Lafon, F. Megret, M. Lafage and C. Prehaud: The innate immune facet of brain: Human neurons express tlr-3 and sense viral dsrna. J Mol Neurosci 29,185-194 (2006)
doi:10.1385/JMN:29:3:185
46. Y. Ma, J. Li, I. Chiu, Y. Wang, J.A. Sloane, J. Lu, B. Kosaras, R.L. Sidman, J.J. Volpe and T. Vartanian:Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175,209-215 (2006)
doi:10.1083/jcb.200606016
PMid:17060494 PMCid:2064562
47. S.C. Tang, T.V. Arumugam, X. Xu, A. Cheng, M.R. Mughal, D.G. Jo, J.D. Lathia, D.A. Siler, S. Chigurupati, X. Ouyang, T. Magnus, S. Camandola and M.P. Mattson: Pivotal role for neuronal toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 104,13798-13803 (2007)
doi:10.1073/pnas.0702553104
PMid:17693552 PMCid:1959462
48. S.C. Tang, J.D. Lathia, P.K. Selvaraj, D.G. Jo, M.R. Mughal, A. Cheng, D.A. Siler, W.R. Markesbery, T.V. Arumugam and M.P. Mattson: Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213,114-121 (2008)
doi:10.1016/j.expneurol.2008.05.014
PMid:18586243 PMCid:2597513
49. S.L. Stevens, T.M. Ciesielski, B.J. Marsh, T. Yang, D.S. Homen, J.L. Boule, N.S. Lessov, R.P. Simon and M.P. Stenzel-Poore: Toll-like receptor 9: A new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab. 28,1040-1047 (2008)
doi:10.1038/sj.jcbfm.9600606
50. R.N. Aravalli, P.K. Peterson and J.R. Lokensgard: Toll-like receptors in defense and damage of the central nervous system. J Neuroimmune Pharmacol 2,297-312 (2007)
doi:10.1007/s11481-007-9071-5
PMid:18040848
51. C. Prehaud, F. Megret, M. Lafage and M. Lafon: Virus infection switches tlr-3-positive human neurons to become strong producers of beta interferon. J Virol 79,12893-12904 (2005)
doi:10.1128/JVI.79.20.12893-12904.2005
PMid:16188991 PMCid:1235836
52. M. Bsibsi, R. Ravid, D. Gveric and J.M. van Noort: Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61,1013-1021 (2002)
PMid:12430718
53. Y.C. Lu, W.C. Yeh and P.S. Ohashi: Lps/tlr4 signal transduction pathway. Cytokine 42,145-151 (2008)
doi:10.1016/j.cyto.2008.01.006
PMid:18304834
54. T.V. Arumugam, E. Okun, S.C. Tang, J. Thundyil, S.M. Taylor and T.M. Woodruff: Toll-like receptors in ischemia-reperfusion injury. Shock. 32,4-16 (2009)
doi:10.1097/SHK.0b013e318193e333
PMid:19008778
55. A. Tsung, R. Sahai, H. Tanaka, A. Nakao, M.P. Fink, M.T. Lotze, H. Yang, J. Li, K.J. Tracey, D.A. Geller and T.R. Billiar: The nuclear factor hmgb1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 201,1135-1143 (2005)
doi:10.1084/jem.20042614
PMid:15795240 PMCid:2213120
56. J.S. Park, J. Arcaroli, H.K. Yum, H. Yang, H. Wang, K.Y. Yang, K.H. Choe, D. Strassheim, T.M. Pitts, K.J. Tracey and E. Abraham: Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol 284,C870-879 (2003)
57. J.S. Park, F. Gamboni-Robertson, Q. He, D. Svetkauskaite, J.Y. Kim, D. Strassheim, J.W. Sohn, S. Yamada, I. Maruyama, A. Banerjee, A. Ishizaka and E. Abraham: High mobility group box 1 protein interacts with multiple toll-like receptors. Am J Physiol Cell Physiol 290,C917-924 (2006)
doi:10.1152/ajpcell.00401.2005
PMid:16267105
58. S. Akira and K. Takeda: Toll-like receptor signalling. Nat Rev Immunol 4,499-511 (2004)
doi:10.1038/nri1391
PMid:15229469
59. M. Karin and Y. Ben-Neriah: Phosphorylation meets ubiquitination: The control of nf- (kappa)b activity. Annu Rev Immunol 18,621-663 (2000)
doi:10.1146/annurev.immunol.18.1.621
PMid:10837071
60. Y. Sha, J. Zmijewski, Z. Xu and E. Abraham: Hmgb1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol 180,2531-2537 (2008)
PMid:18250463
61. J.H. Youn, Y.J. Oh, E.S. Kim, J.E. Choi and J.S. Shin: High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to cd14 and enhances lipopolysaccharide-mediated tnf-alpha production in human monocytes. J Immunol 180,5067-5074 (2008)
PMid:18354232
62. F. Hua, J. Wang, I. Sayeed, T. Ishrat, F. Atif and D.G. Stein:The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice. Biochem Biophys Res Commun 390,678-683 (2009)
doi:10.1016/j.bbrc.2009.10.027
PMid:19825364
63. R.S. Goldstein, M. Gallowitsch-Puerta, L. Yang, M. Rosas-Ballina, J.M. Huston, C.J. Czura, D.C. Lee, M.F. Ward, A.N. Bruchfeld, H. Wang, M.L. Lesser, A.L. Church, A.H. Litroff, A.E. Sama and K.J. Tracey: Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia. Shock 25,571-574 (2006)
doi:10.1097/01.shk.0000209540.99176.72
PMid:16721263
64. U. Kilic, E. Kilic, C.M. Matter, C.L. Bassetti and D.M. Hermann: Tlr-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiol Dis 31,33-40 (2008)
doi:10.1016/j.nbd.2008.03.002
PMid:18486483
65. J.R. Caso, J.M. Pradillo, O. Hurtado, J.C. Leza, M.A. Moro and I. Lizasoain: Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke 39,1314-1320 (2008)
doi:10.1161/STROKEAHA.107.498212
PMid:18309167
66. J.M. Pradillo, D. Fernandez-Lopez, I. Garcia-Yebenes, M. Sobrado, O. Hurtado, M.A. Moro and I. Lizasoain: Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning. J Neurochem 109,287-294 (2009)
doi:10.1111/j.1471-4159.2009.05972.x
PMid:19200341
67. B.J. Marsh, R.L. Williams-Karnesky and M.P. Stenzel-Poore: Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158,1007-1020 (2009)
doi:10.1016/j.neuroscience.2008.07.067
PMid:18809468
68. T.P. Obrenovitch: Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 88,211-247 (2008)
doi:10.1152/physrev.00039.2006
PMid:18195087
69. H.L. Rosenzweig, M. Minami, N.S. Lessov, S.C. Coste, S.L. Stevens, D.C. Henshall, R. Meller, R.P. Simon and M.P. Stenzel-Poore:Endotoxin preconditioning protects against the cytotoxic effects of tnfalpha after stroke: A novel role for tnfalpha in lps-ischemic tolerance. J Cereb Blood Flow Metab 27,1663-1674 (2007)
doi:10.1038/sj.jcbfm.9600464
70. L. Ulloa: The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4,673-684 (2005)
doi:10.1038/nrd1797
PMid:16056392
71. L. Ulloa and D. Messmer: High-mobility group box 1 (hmgb1) protein: Friend and foe. Cytokine Growth Factor Rev 17,189-201 (2006)
doi:10.1016/j.cytogfr.2006.01.003
72. L. Ulloa and K.J. Tracey: The "Cytokine profile": A code for sepsis. Trends Mol Med 11,56-63 (2005)
doi:10.1016/j.molmed.2004.12.007
PMid:15694867
73. H. Yang, M. Ochani, J. Li, X. Qiang, M. Tanovic, H.E. Harris, S.M. Susarla, L. Ulloa, H. Wang, R. DiRaimo, C.J. Czura, H. Wang, J. Roth, H.S. Warren, M.P. Fink, M.J. Fenton, U. Andersson and K.J. Tracey: Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 101,296-301 (2004)
doi:10.1073/pnas.2434651100
PMid:14695889 PMCid:314179
74. G. Sitia, M. Iannacone, S. Muller, M.E. Bianchi and L.G. Guidotti. Treatment with hmgb1 inhibitors diminishes ctl-induced liver disease in hbv transgenic mice. J Leukoc Biol 81,100-107 (2007)
doi:10.1189/jlb.0306173
PMid:16935945
75. R. Kokkola, J. Li, E. Sundberg, A.C. Aveberger, K. Palmblad, H. Yang, K.J. Tracey, U. Andersson and H.E. Harris: Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum 48,2052-2058 (2003)
doi:10.1002/art.11161
76. J.R. Klune, T.R. Billiar and A: Tsung. Hmgb1 preconditioning: Therapeutic application for a danger signal? J Leukoc Biol 83,558-563 (2008)
doi:10.1189/jlb.0607406
PMid:17938274
77. K. Izuishi, A. Tsung, G. Jeyabalan, N.D. Critchlow, J. Li, K.J. Tracey, R.A. Demarco, M.T. Lotze, M.P. Fink, D.A. Geller and T.R. Billiar: Cutting edge: High-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury. J Immunol 176,7154-7158 (2006)
PMid:16751357
78. Q. Yang, Q. Zhong, C. Cao, J. Li, F. Lu and J. Wang: Anti-Toll Like Receptor 4 monoclonal antibody attenuates cerebral ischemia-reperfusion injury. Cerebrovasc Dis 26,217-218 (2008)
79. K. Tasaki, C.A. Ruetzler, T. Ohtsuki, D. Martin, H. Nawashiro and J.M. Hallenbeck:Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. Brain Res 748,267-270 (1997)
doi:10.1016/S0006-8993(96)01383-2
80. H.L. Rosenzweig, N.S. Lessov, D.C. Henshall, M. Minami, R.P. Simon and M.P. Stenzel-Poore: Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 35,2576-2581 (2004)
doi:10.1161/01.STR.0000143450.04438.ae
PMid:15375302
81. E.J. Hickey, X. You, V. Kaimaktchiev, M. Stenzel-Poore and R.M. Ungerleider: Lipopolysaccharide preconditioning induces robust protection against brain injury resulting from deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 133,1588-1596 (2007)
doi:10.1016/j.jtcvs.2006.12.056
PMid:17532961
82. A. Kunz, L. Park, T. Abe, E.F. Gallo, J. Anrather, P. Zhou and C. Iadecola: Neurovascular protection by ischemic tolerance: Role of nitric oxide and reactive oxygen species. J Neurosci 27,7083-7093 (2007)
doi:10.1523/JNEUROSCI.1645-07.2007
PMid:17611261
83. R. Bordet, D. Deplanque, P. Maboudou, F. Puisieux, Q. Pu, E. Robin, A. Martin, M. Bastide, D. Leys, M. Lhermitte, B. Dupuis: Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 20,1190-1196 (2000)
doi:10.1097/00004647-200008000-00004
84. K. Kikuchi, K. Kawahara, K.K. Biswas, T. Ito, S. Tancharoen, Y. Morimoto, F. Matsuda, Y. Oyama, K. Takenouchi, N. Miura, N. Arimura, Y. Nawa, X. Meng, B. Shrestha, S. Arimura, M. Iwata, K. Mera, H. Sameshima, Y. Ohno, R. Maenosono, Y. Yoshida, Y. Tajima, H. Uchikado, T. Kuramoto, K. Nakayama, M. Shigemori, T. Hashiguchi and I. Maruyama: Minocycline attenuates both ogd-induced hmgb1 release and hmgb1-induced cell death in ischemic neuronal injury in pc12 cells. Biochem Biophys Res Commun 385,132-136 (2009)
doi:10.1016/j.bbrc.2009.04.041
PMid:19379716
85. K. Hayakawa, K. Mishima, M. Nozako, M. Hazekawa, S. Mishima, M. Fujioka, K. Orito, N. Egashira, K. Iwasaki abd M. Fujiwara:Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke 39,951-958 (2008)
doi:10.1161/STROKEAHA.107.495820
PMid:18258837
86. K. Kikuchi, K. Kawahara, S. Tancharoen, F. Matsuda, Y. Morimoto, T. Ito, K.K. Biswas, K. Takenouchi, N. Miura, Y. Oyama, Y. Nawa, N. Arimura, M. Iwata, Y. Tajima, T. Kuramoto, K. Nakayama, M. Shigemori, Y. Yoshida, T. Hashiguchi and I. Maruyama: The free radical scavenger edaravone rescues rats from cerebral infarction by attenuating the release of high-mobility group box-1 in neuronal cells. J Pharmacol Exp Ther 329,865-874 (2009)
doi:10.1124/jpet.108.149484
PMid:19293391
87. A.E. Medvedev, A. Lentschat, L.M. Wahl, D.T. Golenbock and S.N. Vogel: Dysregulation of lps-induced toll-like receptor 4-myd88 complex formation and il-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 169,5209-5216 (2002)
PMid:12391239
Key Words: HMGB1, TLR4, Ischemia, Inflammation, Neuroprotection, Review
Send correspondence to: Qing-Wu Yang, Department of Neurology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China, Tel: 86-23-68757842, Fax: 86-23-68792381, E-mail:Yangqwmlys@hotmail.com