Non-canonical inflammasome activation targets caspase-11

• Published in: Nature (London) Vol. 479; no. 7371; pp. 117 - 121
• Main Authors: Kayagaki, Nobuhiko, Warming, Søren, Lamkanfi, Mohamed, Walle, Lieselotte Vande, Louie, Salina, Dong, Jennifer, Newton, Kim, Qu, Yan, Liu, Jinfeng, Heldens, Sherry, Zhang, Juan, Lee, Wyne P., Roose-Girma, Merone, Dixit, Vishva M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.11.2011; Nature Publishing Group
• Subjects: 631/250/256/2177; 631/250/262; 631/45/612/1234; 631/80/86; Animals; Bacterial diseases; Biological and medical sciences; Caspase 1 - metabolism; Caspases - genetics; Caspases - metabolism; Citrobacter rodentium - immunology; Deoxyribonucleic acid; DNA; E coli; Enzyme Activation; Escherichia coli - immunology; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Immune response; Immunity, Innate - immunology; Inflammasomes - metabolism; Inflammation; Interleukin-1beta - biosynthesis; Interleukin-1beta - secretion; letter; Lipopolysaccharides - adverse effects; Lipopolysaccharides - immunology; Macrophages - immunology; Macrophages - secretion; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Molecular and cellular biology; multidisciplinary; Proteins; Science; Science (multidisciplinary); Stem cells; Vibrio cholerae - immunology; Belgium; United States; Peptidases; Vertebrata; Mammalia; Mouse; Enzyme; Rodentia; Caspase; Hydrolases; Activation; Inflammation; Inflammasome
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10558

Key role for caspase-11 in innate immunity It has long been presumed that caspase-11 is pro-inflammatory because of its homology to caspase-1, but its actual role has been enigmatic. Vishva Dixit and co-workers now report a crucial role for caspase-11 in inflammasome activation by various pathogenic Gram-negative bacteria, and show that lipopolysaccharide toxicity depends on caspase-11 — not on caspase-1 as previously thought. This work highlights a pro-inflammatory role for caspase-11 in the innate immune response to bacterial infections. 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 1 , 2 , 3 , 4 , 5 . Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4) 6 , 7 , 8 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 9 , 10 . 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.