Neutralization of pro-inflammatory monocytes by targeting TLR2/6 dimerization ameliorates DSS-induced acute colitis.

Rare Ly6Chi monocytes are present in the healthy intestinal lamina propria, where they give rise to resident CX3CR1+ macrophages that contribute to the maintenance of gut homeostasis. The same cells massively infiltrate the gut during challenge and become pro-inflammatory cells, recruited via CCR2 activated by TLR2 ligation. During DSS-induced colitis, these Ly6Chi monocyte-derived cells cause major damage to the tissue, including ulceration and sub-mucosal inflammation ¹. Here, we report a novel strategy to block TLR2 activation by inhibiting TLR2-TLR6 heterodimerization with the help of a TLR2 trans-membrane domain peptide (TLR2-p) ². Intra-peritoneal TLR2-p injection significantly ameliorated acute gut inflammation in DSS-treated mice. Reduction of colitis scores was accompanied by decrease of IL-23, IL-6, IL-12 and IFNg in the colon without affecting monocyte dynamics in the inflamed colon. Analysis of Ly6Chi monocytes isolated from gut of TLR2-p-treated mice revealed their decreased production of pro-inflammatory cytokines. Collectively, our data highlight the potential of TLR2-p treatment and blockade of TLR dimerization, as a novel therapeutic modality for inflammatory bowel disease (IBD).

Ref.: (1) Zigmond, E. et al. Immunity 37, 1076 (2012); (2).Fink, A. et al. JI 190, 6410 (2013).