Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

Ruochan Chen, Sha Fu, Xue Gong Fan, Michael T. Lotze, Herbert J. Zeh, Daolin Tang, Rui Kang

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-l-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death.

Original languageEnglish (US)
Pages (from-to)650-655
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume458
Issue number3
DOIs
StatePublished - Mar 13 2015

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Keywords

  • Akt
  • DNA
  • HMGB1
  • Histone
  • RAGE
  • TNFα

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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