title: Non-canonical inflammasome activation targets caspase-11.
abstract: Caspase-1 activation by inflammasome scaffolds comprised of intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the adaptor ASC is believed to be essential for production of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 during the innate immune response. Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4) is critical for caspase-1 activation and IL-1β production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11(-/-) mice, exhibited defects in IL-1β production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression. This finding is important because published targeting of the Casp1 gene was done using strain 129 embryonic stem cells. Casp1 and Casp11 are too close in the genome to be segregated by recombination; consequently, the published Casp1(-/-) mice lack both caspase-11 and caspase-1. Interestingly, Casp11(-/-) macrophages secreted IL-1β normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1(-/-)Casp11(129mt/129mt) macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1β regardless of stimulus, confirming an essential role for caspase-1 in IL-1β production. Caspase-11 rather than caspase-1, however, was required for non-canonical inflammasome-triggered macrophage cell death, indicating that caspase-11 orchestrates both caspase-1-dependent and -independent outputs. Caspase-1 activation by non-canonical stimuli required NLRP3 and ASC, but caspase-11 processing and cell death did not, implying that there is a distinct activator of caspase-11. Lastly, loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide. These data highlight a unique pro-inflammatory role for caspase-11 in the innate immune response to clinically significant bacterial infections.
authors: Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA. kayagaki@gene.com
authors: Nobuhiko
authors: N
authors: Kayagaki
authors: Søren
authors: S
authors: Warming
authors: Mohamed
authors: M
authors: Lamkanfi
authors: Lieselotte
authors: L
authors: Vande Walle
authors: Salina
authors: S
authors: Louie
authors: Jennifer
authors: J
authors: Dong
authors: Kim
authors: K
authors: Newton
authors: Yan
authors: Y
authors: Qu
authors: Jinfeng
authors: J
authors: Liu
authors: Sherry
authors: S
authors: Heldens
authors: Juan
authors: J
authors: Zhang
authors: Wyne P
authors: WP
authors: Lee
authors: Merone
authors: M
authors: Roose-Girma
authors: Vishva M
authors: VM
authors: Dixit
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D044082:Citrobacter rodentium / Q000276:immunology; D004789:Enzyme Activation; D004926:Escherichia coli / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D014734:Vibrio cholerae / Q000276:immunology
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1