Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1

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. Salmonella pathogen exploits caspase-11-dependent cell death Most known inflammasomes — multiprotein complexes central to innate immunity — induce cell death by activating pro-inflammatory caspase-1. The recent discovery of a subset of inflammasomes that targets caspase-11 prompted new directions of research in the field. This study of the roles of caspase-1 and -11 during Salmonella infections in mice, a model intracellular infection, shows that activation of caspase-11 by S. enterica Typhimurium, in the absence of immunity induced by caspase-1, contributes to bacterial spread and pathogenesis by inducing macrophage cell death. It will be important to determine whether caspase-11 activation has similar detrimental effects for the host in other infectious-disease models. 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 2 . Recently, a new non-canonical inflammasome was described that activates caspase-11, a pro-inflammatory caspase required for lipopolysaccharide-induced lethality 3 . 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 3 , 4 , 5 , 6 . Previous studies have shown that these mice are more susceptible to infections with microbial pathogens 1 , including the bacterial pathogen Salmonella enterica serovar Typhimurium ( S. typhimurium ) 7 , 8 , 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 o