title: Noncanonical inflammasome activation by intracellular LPS independent of TLR4.
abstract: Gram-negative bacteria including Escherichia coli, Citrobacter rodentium, Salmonella typhimurium, and Shigella flexneri are sensed in an ill-defined manner by an intracellular inflammasome complex that activates caspase-11. We show that macrophages loaded with synthetic lipid A, E. coli lipopolysaccharide (LPS), or S. typhimurium LPS activate caspase-11 independently of the LPS receptor Toll-like receptor 4 (TLR4). Consistent with lipid A triggering the noncanonical inflammasome, LPS containing a divergent lipid A structure antagonized caspase-11 activation in response to E. coli LPS or Gram-negative bacteria. Moreover, LPS-mutant E. coli failed to activate caspase-11. Tlr4(-/-) mice primed with TLR3 agonist polyinosinic:polycytidylic acid [poly(I:C)] to induce pro-caspase-11 expression were as susceptible as wild-type mice were to sepsis induced by E. coli LPS. These data unveil a TLR4-independent mechanism for innate immune recognition of LPS.
authors.affiliation: Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. kayagaki@gene.com
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wong
authors.forename: Irma B
authors.initials: IB
authors.lastname: Stowe
authors.forename: Sree Ranjani
authors.initials: SR
authors.lastname: Ramani
authors.forename: Lino C
authors.initials: LC
authors.lastname: Gonzalez
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akashi-Takamura
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Artur
authors.initials: A
authors.lastname: Muszyński
authors.forename: Lennart S
authors.initials: LS
authors.lastname: Forsberg
authors.forename: Russell W
authors.initials: RW
authors.lastname: Carlson
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D020169:Caspases / Q000096:biosynthesis; D053471:Caspases, Initiator; D002772:Cholera Toxin / Q000276:immunology; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D008050:Lipid A / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D018805:Sepsis / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D058847:Inflammasomes; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002772:Cholera Toxin; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator