Macrophage activation redirects Yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis

Tessa Bergsbaken, Brad T. Cookson

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and naïve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ- Yersinia pseudotuberculosis (Yptb). YopJ- Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis.

Original languageEnglish (US)
Pages (from-to)1570-1582
Number of pages13
JournalPLoS pathogens
Volume3
Issue number11
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

Yersinia
Caspase 1
Macrophage Activation
Cell Death
Macrophages
Apoptosis
Yersinia pseudotuberculosis Infections
Yersinia Infections
Yersinia pseudotuberculosis
Toll-Like Receptors
Lipopolysaccharides
Ligands
Interleukin-18
Pyroptosis
Infection
Caspase 3
DNA Damage
Permeability
Bacteria
Membranes

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

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title = "Macrophage activation redirects Yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis",
abstract = "Infection of macrophages by Yersinia species results in YopJ-dependent apoptosis, and na{\"i}ve macrophages are highly susceptible to this form of cell death. Previous studies have demonstrated that macrophages activated with lipopolysaccharide (LPS) prior to infection are resistant to YopJ-dependent cell death; we found this simultaneously renders macrophages susceptible to killing by YopJ- Yersinia pseudotuberculosis (Yptb). YopJ- Yptb-induced macrophage death was dependent on caspase-1 activation, resulting in rapid permeability to small molecules, followed by membrane breakdown and DNA damage, and accompanied by cleavage and release of proinflammatory interleukin-18. Induction of caspase-1-dependent death, or pyroptosis, required the bacterial type III translocon but none of its known translocated proteins. Wild-type Yptb infection also triggered pyroptosis: YopJ-dependent activation of proapoptotic caspase-3 was significantly delayed in activated macrophages and resulted in caspase-1-dependent pyroptosis. The transition to susceptibility was not limited to LPS activation; it was also seen in macrophages activated with other Toll-like receptor (TLR) ligands and intact nonviable bacteria. Yptb infection triggered macrophage activation and activation of caspase-1 in vivo. Y. pestis infection of activated macrophages also stimulated caspase-1 activation. These results indicate that host signaling triggered by TLR and other activating ligands during the course of Yersinia infection redirects both the mechanism of host cell death and the downstream consequences of death by shifting from noninflammatory apoptosis to inflammatory pyroptosis.",
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Macrophage activation redirects Yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis. / Bergsbaken, Tessa; Cookson, Brad T.

In: PLoS pathogens, Vol. 3, No. 11, 01.11.2007, p. 1570-1582.

Research output: Contribution to journalArticle

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