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Fas (CD95) induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages

Feng Wang1, Ziyue Lu, Michael Hawkes

  • 1Department of Medicine, Toronto General Research Institute, McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada. conrad.liles@uhn.on.ca.

Journal of Inflammation (London, England)
|June 23, 2010
PubMed

Insights

Fas receptor activation triggers rapid release of high mobility group box 1 (HMGB1) from macrophages. This HMGB1 then stimulates pro-inflammatory cytokine production via Toll-like receptor 4 (TLR4) and IRAK4 signaling.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • Fas receptor (CD95) traditionally induces apoptosis.
  • Emerging evidence suggests Fas/FasL system promotes inflammation independently of apoptosis.
  • The exact mechanism of Fas-induced macrophage inflammation remains unclear.

Purpose of the Study:

  • To investigate the role of high mobility group box 1 (HMGB1) in Fas-mediated macrophage inflammation.
  • To elucidate the signaling pathway involved in Fas-induced pro-inflammatory cytokine production.

Main Methods:

  • Fas activation in RAW267.4 cells and primary murine macrophages.
  • Measurement of HMGB1 release and pro-inflammatory cytokine (TNF, MIP-2) production.
  • Utilized anti-HMGB1 antibodies and knockout macrophages (Tlr4-/-, Irak4-/-, Tlr2-/-).

Main Results:

  • Fas activation rapidly released HMGB1 from viable macrophages within 1 hour.
  • Neutralization of HMGB1 significantly reduced Fas-induced TNF and MIP-2 production.
  • Fas-induced HMGB1 release and cytokine production were dependent on Toll-like receptor 4 (TLR4) and IRAK4, but not TLR2.

Conclusions:

  • Fas receptor activation induces rapid, TLR4/IRAK4-dependent release of HMGB1.
  • Released HMGB1 contributes to pro-inflammatory cytokine production by viable macrophages.
  • Identifies a novel mechanism for Fas-mediated inflammatory responses in macrophages.

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