HMGB1, a Novel Cytokine-Like Mediator Linking Acute Neuronal Death and Delayed Neuroinflammation in the Postischemic Brain

Kim, Jung-Bin; Choi, Ji Soo; Yu, Young-Mi; Nam, Ki Woong; Piao, Chunshu; Kim, Seung-Woo; Lee, Min Hyung; Han, Pyung Lim; Park, Jong‐Sang; Lee, Ja-Kyeong

doi:10.1523/jneurosci.3815-05.2006

Cited by 521 publications

(510 citation statements)

References 38 publications

(47 reference statements)

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“…The presence of HMGB-1 in rat cisterna magna fluid probably reflects its release and diffusion from ischemic tissue. We did not detect any HMGB-1 in mouse plasma in contrast to a study in the rat (Kim et al, 2006).…”

Section: Discussioncontrasting

confidence: 99%

“…Here, we suggest that HMGB-1 is released from the ischemic brain parenchyma within 1 h after MCAO, based on early loss of HMGB-1 immunoreactivity in the striatum. Kim et al (2006) showed that HMGB-1 was not hyperacetylated, suggesting that its release is passive. Our demonstration that HMGB-1 is present in rat CSF is also in agreement with Kim et al (2006), who detected this protein 3 h after transient MCAO.…”

Section: Discussionmentioning

confidence: 99%

“…Kim et al (2006) showed that HMGB-1 was not hyperacetylated, suggesting that its release is passive. Our demonstration that HMGB-1 is present in rat CSF is also in agreement with Kim et al (2006), who detected this protein 3 h after transient MCAO. We further show that neurons are one of the principal sources of HMGB-1 release in the early stages of ischemic injury.…”

Section: Discussionmentioning

confidence: 99%

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Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Qiu

Nakagawa

Wang

et al. 2007

J Cereb Blood Flow Metab

366

299

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The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor a (TNFa). Anti-HMGB-1 antibody suppressed TNFa upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFa and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Qiu

Nakagawa

Wang

et al. 2007

J Cereb Blood Flow Metab

366

299

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“…Recent studies have shown that the high-mobility group box 1 (HMGB1) protein, an abundant nuclear protein that acts as an architectural chromatin binding factor, can be passively released by necrotic or damaged cells and serves as a signaling molecule that is involved in acute and chronic inflammation [9,10] . A wealth of evidence indicates that HMGB1 is massively released during the excitotoxicityinduced, acute damaging process in the post-ischemic brain, where it triggers inflammatory processes, and suggests that HMGB1 acts as a novel mediator that links excitotoxicityinduced acute damage and subsequent inflammatory processes in the post-ischemic brain [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Glycyrrhizin attenuates rat ischemic spinal cord injury by suppressing inflammatory cytokines and HMGB1

Gong

Yuan

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the neuroprotective effect of glycyrrhizin (Gly) against the ischemic injury of rat spinal cord and the possible role of the nuclear protein high-mobility group box 1 (HMGB1) in the process. Methods: Male Sprague-Dawley rats were subjected to 45 min aortic occlusion to induce transient lumbar spinal cord ischemia. The motor functions of the animals were assessed according to the modified Tarlov scale. The animals were sacrificed 72 h after reperfusion and the lumbar spinal cord segment (L2-L4) was taken out for histopathological examination and Western blotting analysis. Serum inflammatory cytokine and HMGB1 levels were analyzed using ELISA. Results: Gly (6 mg/kg) administered intravenously 30 min before inducing the transient lumbar spinal cord ischemia significantly improved the hind-limb motor function scores, and reduced the number of apoptotic neurons, which was accompanied by reduced levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the plasma and injured spinal cord. Moreover, the serum HMGB1 level correlated well with the serum TNF-α, IL-1β and IL-6 levels during the time period of reperfusion. Conclusion:The results suggest that Gly can attenuate the transient spinal cord ischemic injury in rats via reducing inflammatory cytokines and inhibiting the release of HMGB1.

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“…In damaged tissue, extracellular HMGB1 acts as a necrotic signal, which alerts the surrounding cells and the immune system. 2 Although extracellular HMGB1 can contribute to normal tissue development and repair, it is also implicated in the pathogenesis of several diseases (including lethal endotoxemia, 7 disseminated intravascular coagulation, 9 ischemic brain, 10 tumor, 11 atherosclerosis, 12 rheumatoid arthritis, 13 and periodontitis 14 ).…”

mentioning

confidence: 99%

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

Arimura

Kii

Hashiguchi

et al. 2009

Laboratory Investigation

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High-mobility group box 1 (HMGB1) protein is a multifunctional protein, which is mainly present in the nucleus and is released extracellularly by dying cells and/or activated immune cells. Although extracellular HMGB1 is thought to be a typical danger signal of tissue damage and is implicated in diverse diseases, its relevance to ocular diseases is mostly unknown. To determine whether HMGB1 contributes to the pathogenesis of retinal detachment (RD), which involves photoreceptor degeneration, we investigated the expression and release of HMGB1 both in a retinal cell death induced by excessive oxidative stress in vitro and in a rat model of RD-induced photoreceptor degeneration in vivo. In addition, we assessed the vitreous concentrations of HMGB1 and monocyte chemoattractant protein 1 (MCP-1) in human eyes with RD. We also explored the chemotactic activity of recombinant HMGB1 in a human retinal pigment epithelial (RPE) cell line. The results show that the nuclear HMGB1 in the retinal cell is augmented by death stress and upregulation appears to be required for cell survival, whereas extracellular release of HMGB1 is evident not only in retinal cell death in vitro but also in the rat model of RD in vivo. Furthermore, the vitreous level of HMGB1 is significantly increased and is correlated with that of MCP-1 in human eyes with RD. Recombinant HMGB1 induced RPE cell migration through an extracellular signalregulated kinase-dependent mechanism in vitro. Our findings suggest that HMGB1 is a crucial nuclear protein and is released as a danger signal of retinal tissue damage. Extracellular HMGB1 might be an important mediator in RD, potentially acting as a chemotactic factor for RPE cell migration that would lead to an ocular pathological wound-healing response.

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HMGB1, a Novel Cytokine-Like Mediator Linking Acute Neuronal Death and Delayed Neuroinflammation in the Postischemic Brain

Cited by 521 publications

References 38 publications

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Glycyrrhizin attenuates rat ischemic spinal cord injury by suppressing inflammatory cytokines and HMGB1

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

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