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

Lan Gu*, Ran Meng, Yiting Tang, Kai Zhao, Fang Liang, Rui Zhang, Qianqian Xue, Fangping Chen, Xianzhong Xiao, Huadong Wang, Haichao Wang, Timothy R. Billiar, Ben Lu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)256-265
Number of pages10
JournalShock
Volume51
Issue number2
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • Caspase-11
  • OMVs
  • noncanonical inflammation
  • sepsis

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