title: A critical role for human caspase-4 in endotoxin sensitivity.
abstract: Response to endotoxins is an important part of the organismal reaction to Gram-negative bacteria and plays a critical role in sepsis and septic shock, as well as other conditions such as metabolic endotoxemia. Humans are generally more sensitive to endotoxins when compared with experimental animals such as mice. Inflammatory caspases mediate endotoxin-induced IL-1β secretion and lethality in mice, and caspase-4 is an inflammatory caspase that is found in the human, and not mouse, genome. To test whether caspase-4 is involved in endotoxin sensitivity, we developed a transgenic mouse expressing human caspase-4 in its genomic context. Caspase-4 transgenic mice exhibited significantly higher endotoxin sensitivity, as measured by enhanced cytokine secretion and lethality following LPS challenge. Using bone marrow-derived macrophages, we then observed that caspase-4 can support activation of caspase-1 and secretion of IL-1β and IL-18 in response to priming signals (LPS or Pam3CSK4) alone, without the need for second signals to stimulate the assembly of the inflammasome. These findings indicate that the regulation of caspase-1 activity by human caspase-4 could represent a unique mechanism in humans, as compared with laboratory rodents, and may partially explain the higher sensitivity to endotoxins observed in humans. Regulation of the expression, activation, or activity of caspase-4 therefore represents targets for systemic inflammatory response syndrome, sepsis, septic shock, and related disorders.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kajiwara
authors.affiliation: Baylor College of Medicine, Houston, TX 77030;
authors.forename: Tamar
authors.initials: T
authors.lastname: Schiff
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Georgios
authors.initials: G
authors.lastname: Voloudakis
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; General Medical Research Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY 10468;
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gama Sosa
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY 10468; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Gregory
authors.initials: G
authors.lastname: Elder
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Ozlem
authors.initials: O
authors.lastname: Bozdagi
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Joseph.Buxbaum@mssm.edu.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D000818:Animals; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D055666:Lipopeptides / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: C508585:IL1B protein, human; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; C093516:CASP4 protein, human; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator