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cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

S McComb1, H H Cheung, R G Korneluk

  • 1NRC-Institute for Biological Sciences, Ottawa, Ontario, Canada.

Cell Death and Differentiation
|May 12, 2012
PubMed

Insights

Cellular inhibitor of apoptosis proteins (cIAPs) prevent programmed necrosis in macrophages. Inhibiting cIAPs leads to macrophage death and impairs the immune response to bacterial infections.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Cellular inhibitor of apoptosis proteins (cIAPs) are key regulators of cell death, particularly in cancer.
  • While cIAPs are present in immune tissues, their precise role in immune function is not fully understood.

Purpose of the Study:

  • To investigate the function of cIAPs in immune cells, specifically macrophages.
  • To elucidate the mechanism by which cIAPs regulate macrophage cell death and immune response.

Main Methods:

  • Utilized SMAC mimetics (SM) to induce degradation of cIAPs in primary bone-marrow-derived macrophages.
  • Assessed macrophage death pathways, including necroptosis, by analyzing TNF receptor expression, Rip1 kinase signaling, and Rip3 knockdown.
  • Investigated the role of xIAP in SM-induced apoptosis and the impact of cIAPs on Rip1 and Rip3 expression.
  • Evaluated the in vivo consequences of reduced cIAP activity on macrophage survival and control of Listeria monocytogenes infection.

Main Results:

  • SM-induced degradation of cIAPs triggered programmed necrosis (necroptosis) in macrophages, dependent on TNF receptor signaling.
  • Necroptosis was mediated by Rip1 kinase and Rip3, and counteracted by the caspase inhibitor xIAP.
  • cIAPs were found to limit Rip3 and Rip1 expression post-transcriptionally, inhibiting necrosome formation.
  • In vivo reduction of cIAP activity led to increased macrophage death and impaired control of Listeria monocytogenes.

Conclusions:

  • cIAPs play a critical role in suppressing programmed necrosis in macrophages.
  • This suppression of necroptosis by cIAPs is essential for effective macrophage-mediated control of intracellular bacterial pathogens.

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