Toll-like receptor 2 (TLR2) recognizes bacterial derived- and synthetic-lipopeptides after dimerization with TLR1 or TLR6. Hyper-activation of TLR2 has been described in several inflammatory diseases and the discovery of inhibitors of its pro-inflammatory activity represent potential starting points to develop therapeutics in such pathologies. We designed peptides derived from the TLR2 sequence comprising amino acid residues involved in ligand binding (Pam3CSK4) or heterodimerization (TLR2/TLR1) as pointed out by structural data.² We identified several peptides (P13, P13(LL), P16, P16(LL)) which inhibited TLR2/1 signaling in HEK293-TLR2 cells (MAPK activation and NF-kB activity). Moreover, P13L and P16L decreased TNFα release in human primary PBMCs and mouse macrophages. The peptides were selective for TLR2/1 as they did not inhibit the activity of other TLRs tested. P13L and P16L inhibited the internalization of Pam3CSK4 fluorescently labeled in macrophages and the heterodimerization of TLR2 with TLR1 as demonstrated by immunoprecipitation studies. Our data demonstrate that peptides derived from the region comprising the leucine-rich repeats (LRR) 11 and 13 in the extracellular domain of TLR2 are good starting points to develop more potent anti-inflammatory peptides with TLR2 inhibitory activity.

Toll样受体2（TLR2）在用TLR1或TLR6二聚化后识别细菌衍生的和合成的脂肽。已经在几种炎性疾病中描述了TLR2的过度活化，并且其促炎活性抑制剂的发现代表了在这种病理学中发展治疗剂的潜在起点。我们设计了由TLR2序列衍生的肽，该肽包含结构数据指出的参与配体结合（Pam3CSK4）或异二聚化（TLR2 / TLR1）的氨基酸残基。^2个我们鉴定了几种肽（P13，P13（LL），P16，P16（LL）），这些肽可抑制HEK293-TLR2细胞中的TLR2 / 1信号传导（MAPK激活和NF-kB活性）。此外，P13L和P16L减少了人原代PBMC和小鼠巨噬细胞中的TNFα释放。该肽对TLR2 / 1具有选择性，因为它们不抑制其他测试的TLR的活性。免疫沉淀研究表明，P13L和P16L抑制了巨噬细胞中荧光标记的Pam3CSK4的内在化以及TLR2与TLR1的异二聚化。我们的数据表明，在TLR2的胞外域中，包含富亮氨酸重复序列（LRR）11和13的区域衍生的肽是开发具有TLR2抑制活性的更有效的抗炎肽的良好起点。