An inhibitory epitope of human Toll-like receptor 4 resides on leucine-rich repeat 13 and is recognized by a monoclonal antibody

FEBS Lett. 2017 Aug;591(16):2406-2416. doi: 10.1002/1873-3468.12768. Epub 2017 Aug 8.

Abstract

Lipopolysaccharide (LPS)-induced activation of Toll-like receptor 4 (TLR4) elicits the innate immune response and can trigger septic shock if excessive. Two antibodies (HT4 and HT52) inhibit LPS-induced human TLR4 activation via novel LPS binding-independent mechanisms. The HT52 epitope resides on leucine-rich repeat 2 (LRR2) and is a feature of many inhibitory antibodies; antigen specificity of HT4 does not reside in LRR2. Here, we identified an HT4 epitope on LRR13 located close to the TLR4 dimerization interface that plays a role in NFκB activation. HT4 and HT52 mutually enhanced TLR4 inhibition. LRR13 is a novel inhibitory epitope and may be useful for developing anti-TLR4 antibodies. Combination therapy with LRR2 and LRR13 may effectively inhibit TLR4 activation.

Keywords: MD-2; Toll-like receptor 4; epitope; inhibitory monoclonal antibody; leucine-rich repeat; lipopolysaccharide.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs*
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Cell Line
  • Epitopes / immunology*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Mice
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Toll-Like Receptor 4 / chemistry*
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 4 / metabolism

Substances

  • Antibodies, Monoclonal
  • Epitopes
  • Lipopolysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4