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Activation of TNFR2 sensitizes macrophages for TNFR1-mediated necroptosis

Daniela Siegmund1, Juliane Kums1, Martin Ehrenschwender2

  • 1Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg 97070, Germany.

Cell Death & Disease
|December 1, 2016
PubMed

Insights

Tumor necrosis factor receptor 2 (TNFR2) sensitizes macrophages to necroptosis, a form of programmed cell death. This sensitization involves TNFR2 interfering with survival pathways, leading to TNF-induced TNFR1-mediated necroptosis.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Macrophages are key immune cells that produce and respond to tumor necrosis factor (TNF).
  • TNF signaling through its receptors, TNFR1 and TNFR2, influences macrophage activity and survival.
  • Understanding the distinct roles of TNFR1 and TNFR2 in TNF-induced macrophage death is crucial.

Purpose of the Study:

  • To investigate the individual contributions of TNFR1 and TNFR2 to TNF-induced cell death in macrophages.
  • To elucidate the mechanisms underlying TNFR1 and TNFR2 involvement in macrophage necroptosis.

Main Methods:

  • Selective stimulation of TNFR1 and TNFR2 in macrophages.
  • Use of caspase inhibitor zVAD-fmk and necrostatin-1 to assess cell death pathways.
  • Analysis of cell death in TNFR1- and TNF-deficient macrophages.
  • Employing SMAC mimetic BV6 to modulate cIAP activity.

Main Results:

  • Selective TNFR2 stimulation caused mild cytotoxicity, enhanced by zVAD-fmk, indicating necroptosis.
  • TNFR1- and TNF-deficient macrophages were resistant to TNFR2-induced cell death.
  • BV6 treatment promoted TNF/TNFR1-mediated necroptosis in the presence of zVAD-fmk.

Conclusions:

  • TNFR2 sensitizes macrophages to TNF-induced TNFR1-mediated necroptosis.
  • TNFR2 likely interferes with TRAF2-cIAP1/2 survival complexes, priming macrophages for necroptosis.
  • This study reveals a novel mechanism for regulating necroptotic cell death in macrophages.

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