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  • 1
    Abstract: Inflammasomes activate the protease caspase-1, which cleaves interleukin-1beta and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1(C284A), we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1(C284A), we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.
    Type of Publication: Journal article published
    PubMed ID: 29281832
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  • 2
    ISSN: 1434-4475
    Keywords: Mass spectrometry ; Metals ; Thermodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Die Thermodynamik flüssiger ternärer Fe1−x(Ni5/6Cr1/6)x-Legierungen wurde mit Hilfe der computerunterstützten Knudsenzellen-Massenspektrometrie studiert. Die thermodynamische Auswertung der experimentellen Untersuchungen erfolgte nach der digitalen Intensitätsverhältnismethode (DIR). Flüssige ternäre Fe1−x(Ni5/6Cr1/6)x-Legierungen zeigen exotherme molare MischungswärmenH E, negative molareGibbssche ZusatzenergienG E, und negative molare ZusatzentropienS E. Bei 1850 K sind die Minimumswerte fürH E −3120 J/mol (42.3 At.% Fe), fürG E −2540 J/mol (30 At.% Fe) und fürS E −0.44 J/(mol K) (60 At.% Fe). Bei 1850 K zeigen die thermodynamischen Aktivitäten von Fe bei Legierungen mit einem Fe-Gehalt von höchstens 75 At.% leichte negative Abweichungen vom idealen Verhalten, die Fe-reichsten Legierungen (x Fe〉0.75) verhalten sich hingegen nahezu ideal.
    Notes: Summary Computer-aidedKnudsen cell mass spectrometry is used for thermodynamic investigations on liquid ternary Fe1−x(Ni5/6Cr1/6)x alloys. The thermodynamic excess properties have been determined by means of the Digital Intensity-Ratio (DIR) method. Liquid ternary Fe1−x(Ni5/6Cr1/6)x alloys are characterized by exothermic molar heats of mixingH E, negative molar excessGibbs energiesG E, and negative molar excess entropiesS E. At 1850 K, the minimumH E value is −3120 J/mol (42.3 at.% Fe), the minimumG E value is −2540 J/mol (30 at.% Fe), and the minimumS E value is −0.44 J/(mol K) (60 at.% Fe). At 1850 K, the thermodynamic activities of Fe show slight negative deviations from the ideal behaviour for alloys with a Fe-content of less than 75 at.%, and ideal behaviour for the Fe-rich alloys (x Fe〉0.75).
    Type of Medium: Electronic Resource
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  • 3
    Publication Date: 2018-11-23
    Description: Pyroptosis is a lytic form of cell death that is induced by inflammatory caspases upon activation of the canonical or noncanonical inflammasome pathways. These caspases cleave gasdermin D (GSDMD) to generate an N-terminal GSDMD fragment, which executes pyroptosis by forming membrane pores. We found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane. Inhibition of the ESCRT-III machinery strongly enhances pyroptosis and interleukin-1β release in both human and murine cells after canonical or noncanonical inflammasome activation. These results not only attribute an anti-inflammatory role to membrane repair by the ESCRT-III system but also provide insight into general cellular survival mechanisms during pyroptosis.
    Keywords: Cell Biology, Immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Nature Publishing Group (NPG)
    Publication Date: 2015-09-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Broz, Petr -- England -- Nature. 2015 Oct 29;526(7575):642-3. doi: 10.1038/nature15632. Epub 2015 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biozentrum, University of Basel, CH-4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26375000" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-08-17
    Description: 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)-1beta and IL-18, as well as lytic inflammatory cell death known as pyroptosis. Recently, a new non-canonical inflammasome was described that activates caspase-11, a pro-inflammatory caspase required for lipopolysaccharide-induced lethality. 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 knockouts. Previous studies have shown that these mice are more susceptible to infections with microbial pathogens, including the bacterial pathogen Salmonella enterica serovar Typhimurium (S. typhimurium), 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-beta (TRIF)-dependent interferon-beta 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470772/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470772/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Broz, Petr -- Ruby, Thomas -- Belhocine, Kamila -- Bouley, Donna M -- Kayagaki, Nobuhiko -- Dixit, Vishva M -- Monack, Denise M -- AI08972/AI/NIAID NIH HHS/ -- AI095396/AI/NIAID NIH HHS/ -- R01 AI089722/AI/NIAID NIH HHS/ -- R01 AI095396/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):288-91. doi: 10.1038/nature11419. Epub 2012 Aug 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895188" target="_blank"〉PubMed〈/a〉
    Keywords: Adjuvants, Immunologic/pharmacology ; Animals ; Caspases/*metabolism ; Cell Death ; Cells, Cultured ; Disease Susceptibility/*enzymology ; Gene Expression Regulation ; Inflammasomes/immunology ; Interferon-gamma/pharmacology ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects/enzymology/microbiology ; Mice ; Mice, Knockout ; Salmonella Infections, Animal/*enzymology/genetics ; Salmonella typhimurium/physiology ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2014-04-18
    Description: 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. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meunier, Etienne -- Dick, Mathias S -- Dreier, Roland F -- Schurmann, Nura -- Kenzelmann Broz, Daniela -- Warming, Soren -- Roose-Girma, Merone -- Bumann, Dirk -- Kayagaki, Nobuhiko -- Takeda, Kiyoshi -- Yamamoto, Masahiro -- Broz, Petr -- England -- Nature. 2014 May 15;509(7500):366-70. doi: 10.1038/nature13157. Epub 2014 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland. ; 1] Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland [2]. ; Department Biomedicine, University of Basel, CH-4056 Basel, Switzerland. ; Genentech Inc., South San Francisco, California 94080, USA. ; Department of Microbiology and Immunology, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739961" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/immunology ; Caspases/*metabolism ; Cytosol/microbiology ; Enzyme Activation ; GTP Phosphohydrolases/*metabolism ; Galectins/immunology ; Gram-Negative Bacteria/growth & development/*immunology/pathogenicity ; Immunity, Innate/immunology ; Inflammasomes/immunology/*metabolism ; Interferon Type I/*immunology ; Lipopolysaccharides/immunology ; Mice ; Phagosomes/immunology/microbiology ; Salmonella typhimurium/growth & development/immunology ; Vacuoles/*microbiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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