Neutralization of pro-inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis

EMBO J. 2016 Mar 15;35(6):685-98. doi: 10.15252/embj.201592649. Epub 2016 Feb 15.

Abstract

Monocytes have emerged as critical driving force of acute inflammation. Here, we show that inhibition of Toll-like receptor 2(TLR2) dimerization by a TLR2 transmembrane peptide (TLR2-p) ameliorated DSS-induced colitis by interfering specifically with the activation of Ly6C(+) monocytes without affecting their recruitment to the colon. We report that TLR2-p directly interacts with TLR2 within the membrane, leading to inhibition of TLR2-TLR6/1 assembly induced by natural ligands. This was associated with decreased levels of extracellular signal-regulated kinases (ERK) signaling and reduced secretion of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-23, IL-12, and IL-1β. Altogether, our study provides insights into the essential role of TLR2 dimerization in the activation of pathogenic pro-inflammatory Ly6C(hi) monocytes and suggests that inhibition of this aggregation by TLR2-p might have therapeutic potential in the treatment of acute gut inflammation.

Keywords: TLR2; Toll‐like receptor; colitis; monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / analysis
  • Colitis / chemically induced
  • Colitis / pathology*
  • Colon / immunology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Immunophenotyping
  • MAP Kinase Signaling System
  • Mice, Inbred C57BL
  • Monocytes / chemistry
  • Monocytes / drug effects*
  • Monocytes / immunology*
  • Protein Multimerization*
  • Toll-Like Receptor 2 / antagonists & inhibitors*
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 6 / metabolism

Substances

  • Antigens, Ly
  • Cytokines
  • Ly-6C antigen, mouse
  • Tlr2 protein, mouse
  • Tlr6 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 6