Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4

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Science  25 Jul 2013:
DOI: 10.1126/science.1240248

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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 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. Notably, Tlr4–/– mice primed with TLR3 agonist poly(I:C) to induce pro-caspase-11 expression were as susceptible as wild-type mice to sepsis induced by E. coli LPS. These data unveil a TLR4-independent mechanism for innate immune recognition of LPS.

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