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Merck

Noncanonical inflammasome activation by intracellular LPS independent of TLR4.

Science (New York, N.Y.) (2013-07-28)
Nobuhiko Kayagaki, Michael T Wong, Irma B Stowe, Sree Ranjani Ramani, Lino C Gonzalez, Sachiko Akashi-Takamura, Kensuke Miyake, Juan Zhang, Wyne P Lee, Artur Muszyński, Lennart S Forsberg, Russell W Carlson, Vishva M Dixit
RESUMEN

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.