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Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated

Sudan He1, Yuqiong Liang, Feng Shao

  • 1Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou 215123, China. hesudan@suda.edu.cn

Proceedings of the National Academy of Sciences of the United States of America
|November 30, 2011
PubMed

Insights

Mouse macrophages undergo receptor-interacting kinase-3 (RIP3)-dependent necrosis via Toll-like receptors (TLR) 3 and 4 activation. This process, essential for innate immunity, involves the TRIF adaptor protein and reactive oxygen species.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Mechanisms of Cell Death

Background:

  • Macrophage necrosis is a critical component of the innate immune response.
  • Toll-like receptors (TLRs) play a key role in recognizing pathogens and initiating immune signaling.
  • Receptor-interacting kinase-3 (RIP3) is a known mediator of programmed necrosis.

Purpose of the Study:

  • To investigate the mechanisms of RIP3-dependent necrosis in macrophages activated by TLRs.
  • To elucidate the role of adaptor proteins, specifically TRIF, in TLR-induced macrophage necrosis.
  • To understand the upstream signaling pathways converging on RIP3 during innate immune responses.

Main Methods:

  • Activation of mouse macrophages with TLR agonists poly(I:C) (TLR3) and LPS (TLR4).
  • Analysis of RIP3 and TRIF involvement in necrosis using knockout mice and protein complex formation studies.
  • Assessment of macrophage loss and inflammatory cytokine levels.
  • Investigation of the role of reactive oxygen species (ROS) in necrosis execution.

Main Results:

  • TLR3 and TLR4 activation induce RIP3-dependent, TNF-α-independent necrosis in mouse macrophages.
  • The adaptor protein TRIF forms a complex with RIP3 upon TLR3/TLR4 activation and is essential for this necrosis.
  • Mice lacking RIP3 or functional TRIF are protected from LPS-induced macrophage loss and cytokine elevation.
  • Necrosis induced by TNFR or TLR3/TLR4 is executed via reactive oxygen species.

Conclusions:

  • Multiple upstream signaling pathways converge on RIP3 for necrosis initiation during innate immune responses to viral and bacterial infections.
  • TRIF is a crucial adaptor protein linking TLR3/TLR4 activation to RIP3-mediated necrosis.
  • ROS are key executioners of necrosis in macrophages activated through TNFR or TLR signaling.

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