Noncanonical inflammasome activation by intracellular LPS independent of TLR4

N Kayagaki, MT Wong, IB Stowe, SR Ramani… - Science, 2013 - science.org
N Kayagaki, MT Wong, IB Stowe, SR Ramani, LC Gonzalez, S Akashi-Takamura, K Miyake…
Science, 2013science.org
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 …
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.
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