Caspase-1-dependent Pore Formation During Pyroptosis Leads to Osmotic Lysis of Infected Host Macrophages

Cell Microbiol. 2006 Nov;8(11):1812-25. doi: 10.1111/j.1462-5822.2006.00751.x. Epub 2006 Jul 4.

Abstract

Salmonella enterica serovar Typhimurium invades host macrophages and induces a unique caspase-1-dependent pathway of cell death termed pyroptosis, which is activated during bacterial infection in vivo. We demonstrate DNA cleavage during pyroptosis results from caspase-1-stimulated nuclease activity. Although poly(ADP-ribose) polymerase (PARP) activation by fragmented DNA depletes cellular ATP to cause lysis during oncosis, the rapid lysis characteristic of Salmonella-infected macrophages does not require PARP activity or DNA fragmentation. Membrane pores between 1.1 and 2.4 nm in diameter form during pyroptosis of host cells and cause swelling and osmotic lysis. Pore formation requires host cell actin cytoskeleton rearrangements and caspase-1 activity, as well as the bacterial type III secretion system (TTSS); however, insertion of functional TTSS translocons into the host membrane is not sufficient to directly evoke pore formation. Concurrent with pore formation, inflammatory cytokines are released from infected macrophages. This mechanism of caspase-1-mediated cell death provides additional experimental evidence supporting pyroptosis as a novel pathway of inflammatory programmed cell death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 1 / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Membrane / microbiology
  • Cells, Cultured
  • Cytokines / metabolism
  • Deoxyribonucleases / metabolism
  • Flow Cytometry
  • Glycine / pharmacology
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Osmosis
  • Salmonella typhimurium / growth & development*

Substances

  • Cytokines
  • Deoxyribonucleases
  • Caspase 1
  • Glycine