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

Stefan M Muehlbauer1, Teresa H Evering, Gloria Bonuccelli

  • 1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Cell Cycle (Georgetown, Tex.)
|March 22, 2007
PubMed

Insights

Anthrax lethal toxin (LT) causes slow apoptosis in resistant macrophages but rapid necrosis in susceptible ones. Caspase-1 activation is key to LT-induced necrosis, potentially driving disease progression.

Area of Science:

  • Immunology
  • Cell Biology
  • Toxicology

Background:

  • Macrophages exhibit varied susceptibility to anthrax lethal toxin (LT) based on genetic background.
  • Human and murine macrophages are generally considered LT-resistant, yet LT can induce cell death.

Purpose of the Study:

  • To investigate the mechanisms of macrophage death induced by anthrax lethal toxin (LT).
  • To determine the role of caspase-1 in LT-mediated macrophage necrosis and disease progression.

Main Methods:

  • Exposure of bone marrow-derived macrophages (BMMs) and splenic macrophages from various mouse strains (DBA/2, AKR, C57BL/6, BALB/c, C3H/HeJ) and human macrophages to LT.
  • Assessment of cell death (apoptosis and necrosis), protein release, and inflammasome/caspase-1 activation.
  • Inhibition of caspase-1 activity to evaluate its role in LT-induced necrosis.

Main Results:

  • LT induced slow apoptosis in macrophages from generally resistant strains (DBA/2, AKR, C57BL/6) and human cells.
  • LT triggered rapid necrosis and protein release, including processed interleukin-18, in BMMs from susceptible strains (BALB/c, C3H/HeJ).
  • Complete caspase-1 inhibition was necessary to block LT-mediated necrosis, highlighting caspase-1's critical role and toxicity.

Conclusions:

  • Caspase-1-mediated macrophage necrosis is a significant pathway for LT toxicity.
  • This necrosis may explain the cytokine storm and rapid disease progression observed in LT-intoxicated BALB/c mice.

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