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

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

Author information

1
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
2
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
3
Department of Biological Services, The Weizmann Institute of Science, Rehovot, Israel.
4
Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel.
5
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel s.jung@weizmann.ac.il yechiel.shai@weizmann.ac.il.
6
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel s.jung@weizmann.ac.il yechiel.shai@weizmann.ac.il.

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

PMID:
26884587
PMCID:
PMC4801944
DOI:
10.15252/embj.201592649
[Indexed for MEDLINE]
Free PMC Article

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