HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain.
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.
Kim
Jung-Bin
JB
Department of Anatomy and Center for Advanced Medical Education (BK21 project), Inha University School of Medicine, Jung-Gu, Inchon 400-712, Republic of Korea.
Sig Choi
Joon
J
Yu
Young-Mi
YM
Nam
Kihoon
K
Piao
Chun-Shu
CS
Kim
Seung-Woo
SW
Lee
Min-Hyung
MH
Han
Pyung-Lim
PL
Park
Jong-Sang
JS
Lee
Ja-Kyeong
JK
D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000633:toxicity; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000378:metabolism* / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000502:physiology; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019311:Staurosporine / Q000633:toxicity; D013997:Time Factors; D014162:Transfection / Q000379:methods
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006609:High Mobility Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D016202:N-Methylaspartate; D019311:Staurosporine