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The Journal of Neuroscience, June 14, 2006, 26(24):6413-6421; doi:10.1523/JNEUROSCI.3815-05.2006

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

Jung-Bin Kim,¹ Joon Sig Choi,² Young-Mi Yu,¹ Kihoon Nam,³ Chun-Shu Piao,¹ Seung-Woo Kim,¹ Min-Hyung Lee,⁴ Pyung-Lim Han,⁵ Jong-sang Park,³ and Ja-Kyeong Lee¹

¹Department of Anatomy and Center for Advanced Medical Education (BK21 project), Inha University School of Medicine, Inchon 400-712, Korea, ²Department of Biochemistry, Chungnam National University, Daejeon 305-764, Korea, ³School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, Korea, ⁴Department of Bioengineering, School of Engineering, Hanyang University, Seoul 133-791, Korea, and ⁵Division of Nano Sciences and Department of Life Sciences, Ewha Womans University, Seoul 110-783, Korea

Correspondence should be addressed to Dr. Ja-Kyeong Lee, Department of Anatomy, Inha University School of Medicine, 7-241 Shinheung-dong, Jung-Gu, Inchon 400-712, Republic of Korea. Email: jklee{at}inha.ac.kr

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.

Key words: HMGB1; MCAO; ischemia; inflammation; shRNA; PAMAM-Arg

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Received Sept. 8, 2005; revised April 11, 2006; accepted April 11, 2006.

Correspondence should be addressed to Dr. Ja-Kyeong Lee, Department of Anatomy, Inha University School of Medicine, 7-241 Shinheung-dong, Jung-Gu, Inchon 400-712, Republic of Korea. Email: jklee{at}inha.ac.kr

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