Induction of TLR4/TLR2 Interaction and Heterodimer Formation by Low Endotoxic Atypical LPS

Front Immunol. 2022 Jan 24:12:748303. doi: 10.3389/fimmu.2021.748303. eCollection 2021.

Abstract

The Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex is considered the major receptor of the innate immune system to recognize lipopolysaccharides (LPSs). However, some atypical LPSs with different lipid A and core saccharide moiety structures and compositions than the well-studied enterobacterial LPSs can induce a TLR2-dependent response in innate immune cells. Ochrobactrum intermedium, an opportunistic pathogen, presents an atypical LPS. In this study, we found that O. intermedium LPS exhibits a weak inflammatory activity compared to Escherichia coli LPS and, more importantly, is a specific TLR4/TLR2 agonist, able to signal through both receptors. Molecular docking analysis of O. intermedium LPS predicts a favorable formation of a TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by fluorescence resonance energy transfer (FRET) in cells. Interestingly, the core saccharide plays an important role in this interaction. This study reveals for the first time TLR4/TLR2 heterodimerization that is induced by atypical LPS and may help to escape from recognition by the innate immune system.

Keywords: Toll-like receptors; atypical-LPS; cytokines; innate immunity; macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Endotoxins / pharmacology*
  • HEK293 Cells
  • Humans
  • Immunity, Innate / drug effects
  • Inflammation / metabolism
  • Lipid A / pharmacology
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Docking Simulation
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Endotoxins
  • Lipid A
  • Lipopolysaccharides
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4