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Synthetic polypeptides inhibit nucleic acid-induced inflammation in autoimmune diseases by disrupting multivalent TLR9 binding to LL37-DNA bundles
Nature Nanotechnology ( IF 38.1 ) Pub Date : 2024-08-19 , DOI: 10.1038/s41565-024-01759-2
Xingliang Liu 1, 2 , Shi Chen 1 , Jing Huang 1, 2 , Yibo Du 1 , Zhi Luo 3 , Yue Zhang 2 , Lixin Liu 1 , Yongming Chen 1, 4, 5, 6
Affiliation  

Complexes of extracellular nucleic acids (NAs) with endogenous proteins or peptides, such as LL37, break immune balance and cause autoimmune diseases, whereas NAs with arginine-enriched peptides do not. Inspired by this, we synthesize a polyarginine nanoparticle PEG-TK-NPArg, which effectively inhibits Toll-like receptor-9 (TLR9) activation, in contrast to LL37. To explore the discrepancy effect of PEG-TK-NPArg and LL37, we evaluate the periodic structure of PEG-TK-NPArg-NA and LL37-NA complexes using small-angle X-ray scattering. LL37-NA complexes have a larger inter-NA spacing that accommodates TLR9, while the inter-NA spacing in PEG-TK-NPArg-NA complexes mismatches with the cavity of TLR9, thus inhibiting an interaction with multiple TLR9s, limiting their clustering and damping immune induction. Subsequently, the inhibitory inflammation effect of PEG-TK-NPArg is proved in an animal model of rheumatoid arthritis. This work on how the scavenger-NA complexes inhibit the immune response may facilitate proof-of-concept research translating to clinical application.



中文翻译:


合成多肽通过破坏多价 TLR9 与 LL37-DNA 束的结合来抑制自身免疫性疾病中核酸诱导的炎症



细胞外核酸 (NA) 与内源性蛋白质或肽(如 LL37)的复合物会破坏免疫平衡并导致自身免疫性疾病,而具有富含精氨酸肽的 NA 则不会。受此启发,我们合成了一种聚精氨酸纳米颗粒 PEG-TK-NP Arg,与 LL37 相比,它有效抑制 Toll 样受体 9 (TLR9) 激活。为了探索 PEG-TK-NP Arg 和 LL37 的差异效应,我们使用小角 X 射线散射评估了 PEG-TK-NP Arg-NA 和 LL37-NA 复合物的周期性结构。LL37-NA 复合物具有更大的 NA 间距,可容纳 TLR9,而 PEG-TK-NP Arg-NA 复合物中的 NA 间距与 TLR9 的空腔错配,从而抑制与多个 TLR9 的相互作用,限制它们的聚集并抑制免疫诱导。随后,在类风湿性关节炎的动物模型中证明了 PEG-TK-NP Arg 的抑制性炎症作用。这项关于清道夫-NA 复合物如何抑制免疫反应的工作可能有助于将概念验证研究转化为临床应用。

更新日期:2024-08-19
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