Shah Masaud, Kim Gi-Young, Achek Asma, Cho Eun-Young, Baek Wook-Young, Choi Yang Seon, Lee Wang Hee, Kim Dong-Jin, Lee Sang Ho, Kim Wook, Kim Soon Sun, Cheong Jae Youn, Suh Chang-Hee, Choi Sangdun
Department of Molecular Science and Technology, Ajou University, Suwon, 16499, South Korea.
Department of Rheumatology, Ajou University School of Medicine, Suwon, 16499, South Korea.
Biomaterials. 2020 Jul;245:119974. doi: 10.1016/j.biomaterials.2020.119974. Epub 2020 Mar 17.
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Toll样受体（TLR）信号传导对于对抗微生物至关重要，但矛盾的是，其信号传导与多种免疫疾病的加重有关，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。衔接蛋白（通过其Toll/白细胞介素-1受体[TIR]结构域）相互作用的化学计量和精确排列对于TLR及其下游信号级联的激活是必不可少的。在衔接蛋白中，质膜锚定的MyD88样衔接蛋白（MAL）具有通过BB环介导的自我寡聚化的潜力，并通过αC和αD螺旋与其他含TIR结构域的衔接蛋白相互作用。在这里，我们利用MAL-αC界面的信息来开发其药效团，并设计一种具有广泛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。通过对动物进行MIP2治疗，标志性血清学和组织生物标志物水平得到显著恢复，疾病症状得到显著改善。总体而言，我们的生物物理、体外和体内研究结果表明，MIP2对TLR具有广泛的特异性，可能有效地调节由微生物或环境因素引起的自身免疫并发症。
