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INNATE IMMUNITY a New Path Uncovers a Wrongful Conviction

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INNATE IMMUNITY a New Path Uncovers a Wrongful Conviction RESEARCH HIGHLIGHTS INNATE IMMUNITY A new path uncovers a wrongful conviction Inflammasomes serve as scaffolds to comparing inflammasome activation initially generated on a 129 back‑ promote the activation of caspase 1 in different mouse strains, they were ground and, owing to the proximity in several and the release of interleukin‑1β surprised to find that macrophages of Casp1 and Casp11 in the mouse disease (IL‑1β) and IL‑18 in response to vari‑ from mice of strain 129 did not genome, have retained the defective ous pro-inflammatory stimuli. Now, secrete IL‑1β in response to CTB. 129‑derived Casp11, despite many models it may Vishva Dixit and co-workers have Screening experiments indicated that generations of backcrossing. To be caspase 11, described a ‘non-canonical’ inflam‑ strain 129 mice have a deficient copy circumvent this difficulty, bacterial rather than masome, which engages caspase 11 of the Casp11 gene, and LPS-primed artificial chromosomes were used to caspase 1, to trigger the caspase 1‑dependent macrophages from caspase 11‑ restore functional Casp11 expression production of pro-inflammatory deficient C57BL/6 mice also failed in caspase 1‑deficient mice. Using that drives cytokines and caspase 1‑independent to secrete IL‑1β in response to CTB, these mice, the authors showed that pathological pyroptosis. despite responding to canonical during non-canonical inflammasome inflammation The authors were exploring activators of the inflammasome, activation caspase 1 is required how cholera enterotoxin subunit B such as ATP, double-stranded DNA for IL‑1β processing but not for (CTB) promotes inflammasome and flagellin. Caspase 11‑deficient macrophage pyroptosis. activation in bone marrow-derived C57BL/6 macrophages secreted Finally, the authors assessed the macrophages primed with lipo­ IL‑1β following infection with relative contributions of caspase 1 polysaccharide (LPS). They showed Francisella tularensis or Pseudomonas and caspase 11 in a model of that this process results in the aeruginosa, but were unable to LPS-induced septic shock. Both processing of caspase 1 in a manner produce IL‑1β after infection with caspase 11‑deficient mice and the dependent on NOD-, LRR- and pyrin Escherichia coli, Citrobacter rodentium double-deficient mice showed domain-containing 3 (NLRP3) and or Vibrio cholerae. This led the increased survival compared with the adaptor protein ASC. However, authors to propose the existence wild-type controls, but mice that of a non-canonical inflammasome, were only deficient for caspase 1 which activates caspase 1 downstream were not protected. By contrast, of caspase 11 engagement. previous studies that had inadvert‑ An important outcome of inflam‑ ently used the double-deficient mice masome assembly and caspase 1 acti‑ suggested that caspase 1 contributed vation is the induction of pyroptosis, to LPS-induced lethality. Thus, the an inflammatory type of cell death. authors’ findings are notable, not The authors found that caspase 11 only for their description of this was not required for macrophage non-canonical pathway of inflam‑ pyroptosis in response to canonical masome activation, but also because activators of the inflammasome, but they highlight the need to re-address was necessary for the induction of other findings made in the original pyroptosis following infection with caspase 1‑deficient mice. Dixit and E. coli, C. rodentium or V. cholerae. colleagues propose that in several Interestingly, NLRP3 and ASC were disease models it may be caspase 11, not needed for caspase 11 to deliver rather than caspase 1, that drives death signals in response to these pathological inflammation. bacteria. Addressing the role of Yvonne Bordon caspase 1 in non-canonical inflam‑ masome activation, the authors ORIGINAL RESEARCH PAPER Kayagaki, N. et al. made a rather startling finding. Non-canonical inflammasome activation targets caspase‑11. Nature 479, 117–121 (2011) IMAGE SOURCE All caspase 1‑deficient mice were NATURE REVIEWS | IMMUNOLOGY VOLUME 11 | DECEMBER 2011 © 2011 Macmillan Publishers Limited. All rights reserved.
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