Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway

Seung Woo Kim, Chae Moon Lim, Jung Bin Kim, Joo Hyun Shin, Sanghyun Lee, Minhyung Lee, Ja Kyeong Lee

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

High mobility group box 1 (HMGB1) was originally identified as ubiquitously expressed nonhistone DNAbinding protein, but recently, it was found to act as an endogenous danger molecule, which signals danger and traumatic cell death. Previously, the authors showed that HMGB1 is massively released immediately after an ischemic insult and that it subsequently activates microglia and induces inflammation in the postischemic brain. Here, we showed the endogenous danger molecule-like function ofHMGB1 in primary cortical cultures. HMGB1 was found to be accumulated in NMDA-treated primary cortical culture media, and media collected from these cultures were able to induce neuronal cell death when added to fresh primary cortical cultures. However, HMGB1-depleted NMDA-conditioned media produced by HMGB1 siRNA transfection or by preincubation with anti-HMGB1 antibody or with HMGB1 A box failed to induce neuronal cell death. Furthermore, siRNA-mediated HMGB1 knockdown substantially suppressed NMDA- or Zn2+-induced cell death. It was interesting to find that extracellular HMGB1-induced neuronal apoptosis, as evidenced by TUNEL staining and caspase 3 assay in combination with double immunofluorescence staining. A series of RAGE andHMGB1 co-immunoprecipitation experiments in the presence of SB203580 and PD98059 (p38 MAPK and ERK inhibitors, respectively) demonstrated that RAGE-p38 MAPK and RAGE-ERK pathway might underlie extracellular HMGB1-mediated neuronal apoptosis. These results together with our previous reports regarding microglial activation by extracellular HMGB1 indicate that HMGB1 functions as a novel danger signal, which aggravates brain damage via autocrine and paracrine manners.

Original languageEnglish
Pages (from-to)159-169
Number of pages11
JournalNeurotoxicity Research
Volume20
Issue number2
DOIs
StatePublished - 2011 Aug 1

Fingerprint

MAP Kinase Signaling System
p38 Mitogen-Activated Protein Kinases
Cell death
N-Methylaspartate
Cell Death
Apoptosis
Small Interfering RNA
Culture Media
Brain
Staining and Labeling
Molecules
In Situ Nick-End Labeling
Microglia
Therapeutics
Conditioned Culture Medium
Cell culture
Immunoprecipitation
Caspase 3
Fluorescent Antibody Technique
Transfection

Keywords

  • Apoptosis
  • HMGB1
  • NMDA-conditioned media
  • Primary cortical culture
  • RAGE

Cite this

Kim, Seung Woo ; Lim, Chae Moon ; Kim, Jung Bin ; Shin, Joo Hyun ; Lee, Sanghyun ; Lee, Minhyung ; Lee, Ja Kyeong. / Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway. In: Neurotoxicity Research. 2011 ; Vol. 20, No. 2. pp. 159-169.
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Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway. / Kim, Seung Woo; Lim, Chae Moon; Kim, Jung Bin; Shin, Joo Hyun; Lee, Sanghyun; Lee, Minhyung; Lee, Ja Kyeong.

In: Neurotoxicity Research, Vol. 20, No. 2, 01.08.2011, p. 159-169.

Research output: Contribution to journalArticle

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