Toll-Like Receptor 4 Signaling Licenses the Cytosolic Transport of Lipopolysaccharide From Bacterial Outer Membrane Vesicles

Shock. 2019 Feb;51(2):256-265. doi: 10.1097/SHK.0000000000001129.


Outer membrane vesicles (OMVs), released by variety of bacteria, are membrane-enclosed entities enriched in microbial components, toxins, and virulent factors. OMVs could deliver lipopolysaccharide (LPS) into the cytosol of host cells and subsequently activate caspase-11, which critically orchestrates immune responses and mediates septic shock. Although it is known that caspase-11 is activated by intracellular LPS, how OMVs deliver LPS into the cytosol remains largely unknown. Here we show that the activation of toll-like receptor 4 (TLR4), a LPS receptor on the cytoplasmic membrane, licenses macrophages to transport LPS from OMVs into the cytosol through TIR domain-containing adaptor-inducing interferon-β (TRIF). TRIF-mediated cytosolic delivery of LPS from OMVs depends on the production of type 1 interferon and the expression of guanylate-binding proteins (GBPs). Deletion of TRIF or GBPs prevents pyroptosis and lethality induced by OMVs or OMVs-releasing Escherichia coli. Together, these findings provide novel insight into how host coordinates extracellular and intracellular LPS sensing to orchestrate immune responses during gram-negative bacterial infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport, Active
  • Cell Membrane / immunology*
  • Escherichia coli / immunology*
  • Extracellular Vesicles / immunology*
  • Lipopolysaccharides* / pharmacokinetics
  • Lipopolysaccharides* / toxicity
  • Macrophages / immunology
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Pyroptosis / drug effects
  • Pyroptosis / genetics
  • Pyroptosis / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*


  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4