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

Abstract

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. 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 pyroptosis2. Recently, a new non-canonical inflammasome was described that activates caspase-11, a pro-inflammatory caspase required for lipopolysaccharide-induced lethality3. 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 knockouts3,4,5,6. Previous studies have shown that these mice are more susceptible to infections with microbial pathogens1, 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 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.