Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4

TLDR

Gram‑negative bacteria are sensed by an intracellular inflammasome that activates caspase‑11, though the sensing mechanism is poorly defined. Macrophages exposed to LPS or lipid A activate caspase‑11 independently of TLR4, and LPS variants with altered lipid A structures fail to trigger this response, demonstrating a TLR4‑independent, noncanonical inflammasome pathway that also renders Tlr4‑/‑ mice susceptible to LPS‑induced sepsis.

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.