Despite being crucial for combating microbes, paradoxical Toll-like receptors (TLRs) signaling have been associated with the aggravation of multiple immune disorders such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, and nonalcoholic steatohepatitis. The stoichiometry and precise arrangement of the interaction of adapters (via their Toll/interleukin-1 receptor [TIR] domains) are indispensable for the activation of TLRs and of downstream signaling cascades. Among adapters, plasma membrane–anchored MyD88 adaptor–like (MAL) has the potential for BB-loop–mediated self-oligomerization and interacts with other TIR domain–containing adaptors through αC and αD helices. Here, we used information on the MAL–αC interface to exploit its pharmacophores and to design a decoy peptide (MIP2) with broad-range TLR-inhibitory abilities. MIP2 abrogated MyD88- and TRIF-dependent lipopolysaccharide (LPS)-induced TLR4 signaling in murine and human cell lines and manifested a therapeutic potential in models of psoriasis, systemic lupus erythematosus, nonalcoholic steatohepatitis, and sepsis. Levels of hallmark serological and histological biomarkers were significantly restored and the disease symptoms were substantially ameliorated by MIP2 treatment of the animals. Collectively, our biophysical, in vitro, and in vivo findings suggest that MIP2 has broad specificity for TLRs and may be effective in modulating autoimmune complications caused by microbial or environmental factors.

尽管对于对抗微生物至关重要，但矛盾的 Toll 样受体 (TLR) 信号传导与多种免疫疾病的恶化有关，例如系统性红斑狼疮、银屑病、类风湿性关节炎和非酒精性脂肪性肝炎。接头相互作用的化学计量和精确排列（通过它们的 Toll/interleukin-1 受体 [TIR] 结构域）对于激活 TLR 和下游信号级联是必不可少的。在接头中，质膜锚定的 MyD88 接头样 (MAL) 具有 BB 环介导的自寡聚化的潜力，并通过 αC 和 αD 螺旋与其他含有 TIR 结构域的接头相互作用。在这里，我们使用有关 MAL-αC 界面的信息来利用其药效团并设计具有广泛 TLR 抑制能力的诱饵肽 (MIP2)。MIP2 消除了小鼠和人类细胞系中 MyD88 和 TRIF 依赖性脂多糖 (LPS) 诱导的 TLR4 信号传导，并在银屑病、系统性红斑狼疮、非酒精性脂肪性肝炎和败血症模型中表现出治疗潜力。通过对动物的 MIP2 治疗，标志性血清学和组织学生物标志物的水平显着恢复，疾病症状显着改善。总的来说，我们的生物物理学，通过对动物的 MIP2 治疗，标志性血清学和组织学生物标志物的水平显着恢复，疾病症状显着改善。总的来说，我们的生物物理学，通过对动物的 MIP2 治疗，标志性血清学和组织学生物标志物的水平显着恢复，疾病症状显着改善。总的来说，我们的生物物理学，体外和体内研究结果表明，MIP2 对 TLR 具有广泛的特异性，并且可能有效调节由微生物或环境因素引起的自身免疫并发症。