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

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.

TRIM58 Restrains Intestinal Mucosal Inflammation by Negatively Regulating TLR2 in Myeloid Cells

“…On the one hand, TLR2 engagement has been shown to be critical for the induction of proinflammatory activities in distinct lamina propria mononuclear subsets in the inflamed gut (8). Blocking TLR2 dimerization in pathogenic Ly-6C hi monocytes ameliorated acute DSS colitis (12). On the other hand, previous work from this laboratory demonstrated that TLR2 plays a key role in maintaining tight-and gap-junction-associated IEC barrier integrity (9,40).…”

“…The inflammatory process must be self-limited to avoid excessive tissue destruction and the development of chronic inflammatory or autoimmune diseases (29). TLR2 plays important roles in initiating diverse cell-specific immune responses in the gastrointestinal tract (8,9,12,30), but the mechanisms that restrain aberrant TLR2 signaling remain to be resolved.…”

“…However, the functional outcome of TLR2 signaling varies considerably between cell types. Although TLR2 activation exerts several important cytoprotective responses in the intestinal epithelium required for cell survival, barrier stability, and mucosal healing (9)(10)(11), TLR2 activation may turn intestinal monocytes into proinflammatory effector cells in the lamina propria (8,12). The mechanisms that maintain cell-specific balance between TLR2 activation and inactivation remain unclear.…”

MyD88 Adapter-like (Mal)/TIRAP Is Required for Cytokine Production by Splenic Ly6CloTLR2hi but Not by Ly6ChiTLR2hi Monocytes during Trypanosoma cruzi Infection

“…Others have previously reported an up-regulation of TLR2 expression on blood monocytes in patients with Kawasaki disease or sepsis, underlining that TLR2 may serve as an inflammatory marker and be responsible for the immunopathogenesis in different situations (30,35,38).…”

Intramembrane attenuation of the TLR4-TLR6 dimer impairs receptor assembly and reduces microglia-mediated neurodegeneration

“…Recent studies proposed that the transmembrane domains (TMDs) of TLR2, TLR6, and TLR1 are involved in the regulation of the receptor's activity (6). Exogenously added peptides that correspond to the TMDs of either TLR2 or TLR6 were able to modulate the activity of these receptors in a mouse sepsis and acute colitis models (7,8).…”