Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis

Stefan M. Muehlbauer, Teresa H. Evering, Gloria Bonuccelli, Raynal C. Squires, Anthony W. Ashton, Steven A. Porcelli, Michael P. Lisanti, Jürgen Brojatsch

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Murine macrophages have been classified as either susceptible or nonsusceptible to killing by anthrax lethal toxin (LT) depending upon genetic background. While considered resistant to LT killing, we found that bone marrow-derived macrophages (BMMs) from DBA/2, AKR, and C57BL/6 mice were slowly killed by apoptosis following LT exposure. LT killing was not restricted to in vitro assays, as splenic macrophages were also depleted in LT-injected C57BL/6 mice. Human macrophages, also considered LT resistant, similarly underwent slow apoptosis in response to LT challenge. In contrast, LT triggered rapid necrosis and broad protein release in BMMs derived from BALB/c and C3H/HeJ, but not C57BL/6 mice. Released proteins included processed interleukin-18, confirming reports of inflammasome and caspase-1 activation in LT-mediated necrosis in macrophages. Complete inhibition of caspase-1 activity was required to block LT-mediated necrosis. Strikingly, minimal residual caspase-1 activity was sufficient to trigger significant necrosis in LT-treated macrophages, indicating the toxicity of caspase-1 in this process. IL-18 release does not trigger cytolysis, as IL-18 is released late and only from LT-treated macrophages undergoing membrane perturbation. We propose that caspase-1-mediated macrophage necrosis is the source of the cytokine storm and rapid disease progression reported in LT-treated BALB/c mice.

Original languageEnglish (US)
Pages (from-to)758-766
Number of pages9
JournalCell Cycle
Volume6
Issue number6
DOIs
StatePublished - Mar 15 2007

Keywords

  • Anthrax
  • Apoptosis
  • Caspase-1
  • Inflammasome
  • Interleukin 18
  • Lethal toxin
  • Macrophage
  • Necrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Muehlbauer, S. M., Evering, T. H., Bonuccelli, G., Squires, R. C., Ashton, A. W., Porcelli, S. A., Lisanti, M. P., & Brojatsch, J. (2007). Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis. Cell Cycle, 6(6), 758-766. https://doi.org/10.4161/cc.6.6.3991