Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages

TLDR

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. 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. During pyroptosis, caspase‑1 activates a nuclease that cleaves DNA, yet rapid lysis of Salmonella‑infected macrophages occurs independently of PARP or DNA fragmentation; membrane pores 1.1–2.4 nm in diameter form, causing swelling, osmotic lysis, and concurrent release of inflammatory cytokines, thereby confirming caspase‑1‑mediated pyroptosis as a distinct inflammatory programmed cell‑death pathway.

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.