**Caspase-11 increases susceptibility toSalmonellainfection in the absence of caspase-1**

Broz, Petr
Ruby, Thomas
Belhocine, Kamila
Bouley, Donna M.
Kayagaki, Nobuhiko
Dixit, Vishva M.
Monack, Denise M.

¹Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, California 94305, USA
²Department of Comparative Medicine Stanford School of Medicine, Stanford University, California 94305, USA
³Genentech Inc., South San Francisco, California 94080, USA

Activation of the non-canonical, pro-inflammatory caspase-11 by Salmonella typhimurium is shown to contribute to bacterial spread and pathogenesis by the induction of macrophage cell death.

Email:[email protected]

Received 27 March 2012; accepted 18 July 2012; Published online 15 August 2012.

Nature 490(7419):p 288-291, October 11, 2012. | DOI: 10.1038/nature11419

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.). 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 ofCasp11(also known asCasp4), making them functionallyCasp1 Casp11double knockouts. Previous studies have shown that these mice are more susceptible to infections with microbial pathogens, including the bacterial pathogenSalmonella entericaserovar 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 duringS. typhimuriuminfection. 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 withS. typhimuriumthan 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.