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

Sanna Nystrom, Daniel J. Antoine, Peter Lundback, John G. Lock, Andreia F. Nita, Kari Hogstrand, Alf Grandien, Helena Erlandsson-Harris, Ulf Andersson, Steven E. Applequist*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Infection of macrophages by bacterial pathogens can trigger Toll-like receptor (TLR) activation as well as Nod-like receptors (NLRs) leading to inflammasome formation and cell death dependent on caspase-1 (pyroptosis). Complicating the study of inflammasome activation is priming. Here, we develop a priming-free NLRC4 inflammasome activation system to address the necessity and role of priming in pyroptotic cell death and damage-associated molecular pattern (DAMP) release. We find pyroptosis is not dependent on priming and when priming is re-introduced pyroptosis is unaffected. Cells undergoing unprimed pyroptosis appear to be independent of mitochondrial involvement and do not produce inflammatory cytokines, nitrous oxide (NO), or reactive oxygen species (ROS). Nevertheless, they undergo an explosive cell death releasing a chemotactic isoform of the DAMP high mobility group protein box 1 (HMGB1). Importantly, priming through surface TLRs but not endosomal TLRs during pyroptosis leads to the release of a new TLR4-agonist cysteine redox isoform of HMGB1. These results show that pyroptosis is dominant to priming signals and indicates that metabolic changes triggered by priming can affect how cell death is perceived by the immune system. The EMBO Journal (2013) 32, 86-99. doi:10.1038/emboj.2012.328; Published online 7 December 2012

Original languageEnglish
Pages (from-to)86-99
Number of pages14
JournalEMBO Journal
Volume32
Issue number1
DOIs
Publication statusPublished - 9 Jan 2013

Keywords

  • HMGB1
  • inflammasome
  • Nod-like receptor C4
  • pyroptosis
  • Toll-like receptor
  • III SECRETION APPARATUS
  • CELL-DEATH
  • INFLAMMASOME ACTIVATION
  • NLRP3 INFLAMMASOME
  • NLRC4 INFLAMMASOME
  • CYTOKINE RELEASE
  • INFECTION
  • CASPASE-1
  • APOPTOSIS

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