Inflammasomes are cytosolic multiprotein complexes assembled by intracellular 
nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and they 
initiate innate immune responses to invading pathogens and danger signals by 
activating caspase-1 (ref. 1). Caspase-1 activation leads to the maturation and 
release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, as well 
as lytic inflammatory cell death known as pyroptosis. Recently, a new 
non-canonical inflammasome was described that activates caspase-11, a 
pro-inflammatory caspase required for lipopolysaccharide-induced lethality. This 
study also highlighted that previously generated caspase-1 knockout mice lack a 
functional allele of Casp11 (also known as Casp4), making them functionally 
Casp1 Casp11 double knockouts. Previous studies have shown that these mice are 
more susceptible to infections with microbial pathogens, including the bacterial 
pathogen Salmonella enterica serovar Typhimurium (S. typhimurium), but the 
individual contributions of caspase-1 and caspase-11 to this phenotype are not 
known. Here we show that non-canonical caspase-11 activation contributes to 
macrophage death during S. typhimurium infection. Toll-like receptor 4 
(TLR4)-dependent and TIR-domain-containing adaptor-inducing interferon-β 
(TRIF)-dependent interferon-β production is crucial for caspase-11 activation in 
macrophages, but is only partially required for pro-caspase-11 expression, 
consistent with the existence of an interferon-inducible activator of 
caspase-11. Furthermore, Casp1(-/-) mice were significantly more susceptible to 
infection with S. typhimurium than mice lacking both pro-inflammatory caspases 
(Casp1(-/-) Casp11(-/-)). This phenotype was accompanied by higher bacterial 
counts, the formation of extracellular bacterial microcolonies in the infected 
tissue and a defect in neutrophil-mediated clearance. These results indicate 
that caspase-11-dependent cell death is detrimental to the host in the absence 
of caspase-1-mediated innate immunity, resulting in extracellular replication of 
a facultative intracellular bacterial pathogen.