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HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2006 Jun 14; Vol. 26 (24), pp. 6413-21. - Publication Year :
- 2006
-
Abstract
- Cerebral ischemic injury proceeds with excitotoxicity-induced acute neuronal death in the ischemic core and with delayed damage processes in the penumbra. However, knowledge concerning the direct mediators that connect these two processes is limited. Here, we demonstrate that high-mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain. Short hairpin (sh)RNA-mediated HMGB1 downregulation in the postischemic brain suppressed infarct size, microglia activation, and proinflammatory marker induction, indicating that HMGB1 plays a crucial role in the inflammatory process. The proinflammatory cytokine-like function of extracellular HMGB1 was further verified in primary cortical cultures and microglial cultures. HMGB1 was found to accumulate in NMDA-treated primary cortical culture media, and supernatants collected from these cultures were found to trigger microglia activation, the hallmark of brain inflammation. Moreover, treatment with recombinant HMGB1 also induced microglial activation, but HMGB1-depleted supernatant produced by anti-HMGB1 antibody treatment or by HMGB1 shRNA expression did not, thus demonstrating the essential role of HMGB1 in microglial activation. Together, these results indicate that HMGB1 functions as a novel proinflammatory cytokine-like factor that connects excitotoxicity-induced acute damage processes and delayed inflammatory processes in the postischemic brain.
- Subjects :
- Animals
Blotting, Northern methods
Blotting, Western methods
Brain pathology
Cell Death physiology
Cells, Cultured
Culture Media, Conditioned pharmacology
Embryo, Mammalian
Enzyme Inhibitors toxicity
Excitatory Amino Acid Agonists toxicity
Gene Expression drug effects
Gene Expression physiology
HMGB1 Protein
High Mobility Group Proteins pharmacology
Infarction, Middle Cerebral Artery complications
Infarction, Middle Cerebral Artery metabolism
Infarction, Middle Cerebral Artery pathology
Inflammation etiology
Male
Mice
Microglia metabolism
Microglia physiology
N-Methylaspartate toxicity
Neurons drug effects
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Repressor Proteins pharmacology
Reverse Transcriptase Polymerase Chain Reaction methods
Staurosporine toxicity
Time Factors
Transfection methods
Brain metabolism
High Mobility Group Proteins metabolism
Inflammation metabolism
Inflammation pathology
Neurons metabolism
Repressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 26
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 16775128
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.3815-05.2006