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TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis

Sanna Nyström1, Daniel J Antoine, Peter Lundbäck

  • 1Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

The EMBO Journal
|December 11, 2012
PubMed

Insights

Pyroptosis, a form of cell death, does not require priming. Unprimed pyroptosis releases damage-associated molecular patterns (DAMPs) like HMGB1, independent of inflammatory signaling or mitochondrial involvement.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Bacterial infections activate Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in macrophages, leading to inflammasome activation and pyroptosis.
  • Priming is a complex process that complicates the study of inflammasome activation and pyroptosis.

Purpose of the Study:

  • To develop a priming-free NLRC4 inflammasome activation system.
  • To investigate the necessity and role of priming in pyroptotic cell death and damage-associated molecular pattern (DAMP) release.

Main Methods:

  • Development of a priming-free NLRC4 inflammasome activation system in macrophages.
  • Analysis of pyroptosis, DAMP release, cytokine production, nitrous oxide (NO), and reactive oxygen species (ROS) with and without priming.

Main Results:

  • Pyroptosis is not dependent on priming and is unaffected by its re-introduction.
  • Unprimed pyroptosis is independent of mitochondrial involvement and does not produce inflammatory cytokines, NO, or ROS.
  • Unprimed pyroptosis releases high mobility group protein box 1 (HMGB1), a DAMP.
  • Priming via surface TLRs, but not endosomal TLRs, during pyroptosis leads to the release of a TLR4-agonist cysteine redox isoform of HMGB1.

Conclusions:

  • Pyroptosis is dominant to priming signals.
  • Metabolic changes induced by priming can influence the immune system's perception of cell death.
  • The study reveals distinct HMGB1 isoforms released during pyroptosis depending on priming status.

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