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Inflammasomes are cytosolic protein complexes that activate caspase-1, an inflammatory protease that converts pro-interleukin (IL)-1β and IL-18 into their secreted, bioactive forms (1); and mechanisms regulating inflammasome activation have attracted [...]

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukm-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from [Gsdmd.sup.-/-] mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, [Gsdmd.sup.-/-] mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediatorof the host response against Gram-negative bacteria., Cytoplasmic caspase-11 (also known as caspase-4) defines the non-canonical inflammasome that is activated by various Gram-negative bacterial infections and causes infected cells to die by pyroptosis (1-4). Caspase-11 also triggers [...]

T-helpertype 17 ([T.sub.H]17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases (1,2). The differentiation of [T.sub.H]17 cells is regulated by [...]

Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death (1-3). In mouse macrophages, activation [...]

NLRC4 is a cytosolic member of the NOD-like receptor family that is expressed in innate immune cells. It senses indirectly bacterial flagellin and type III secretion systems, and responds by [...]

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 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 (1-5). Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4) (6-8) 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.sup.-/-] 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.sup.-/-] mice lack both caspase-11 and caspase-1. Interestingly, [Casp11.sup.-/-] macrophages secreted IL-1β normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. [Casp1.sup.-/-][Casp11.sup.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., Many bacterial toxins promote inflammasome activation (11-15), and this is also true for cholera toxin B (CTB), a component of the AB5 holotoxin complex (Fig. 1a and Supplementary Fig. 1). [...]