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

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. Synopsis Here, we utilize a novel strategy to neutralized TLR2 activation by inhibiting its dimerization by TLR2 transmembrane-derived peptide (TLR2-p). We show that TLR-2 peptide ameliorated DSS-induced colitis by interfering specifically with the activation of Ly6C⁺ monocytes without affecting their recruitment to the colon. The TLR2 transmembrane-derived peptide (TLR2-p) inhibits TLR2 signaling by interacting with its reciprocal receptors within the membrane. TLR2-p inhibits the dimerization of TLR2-TLR6/1 induced by natural ligands, resulting in attenuation of pro-inflammatory downstream signaling. Inhibition of TLR2 dimerization ameliorates acute colitis. TLR2-p inhibits TLR2 signaling in pathogenic pro-inflammatory Ly6C^hi monocytes without affecting their recruitment to the inflamed gut. A novel approach for blocking TLR2 signaling modulates immune cell activation and reduces disease severity during acute gut inflammation.