Tonsillar Microbiome-Derived Lantibiotics Induce Structural Changes of IL-6 and IL-21 Receptors and Modulate Host Immunity.
Tonsillar Microbiome-Derived Lantibiotics Induce Structural Changes of IL-6 and IL-21 Receptors and Modulate Host Immunity.
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扁桃体微生物组 - 羊毛硫抗生素可诱导 IL-6 和 IL-21 受体的结构变化并调节宿主免疫
DOI：
10.1002/advs.202202706
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发表时间：
2022-10
期刊：
影响因子：
15.1
通讯作者：
Li, Zhanguo
中科院分区：
文献类型：
--
作者：
Li, Jing;Jin, Jiayang;Li, Shenghui;Zhong, Yan;Jin, Yuebo;Zhang, Xuan;Xia, Binbin;Zhu, Yinhua;Guo, Ruochun;Sun, Xiaolin;Guo, Jianping;Hu, Fanlei;Xiao, Wenjing;Huang, Fei;Ye, Hua;Li, Ru;Zhou, Yunshan;Xiang, Xiaohong;Yao, Haihong;Yan, Qiulong;Su, Li;Wu, Lijun;Luo, Tuoping;Liu, Yudong;Guo, Xiaohuan;Qin, Junjie;Qi, Hai;He, Jing;Wang, Jun;Li, Zhanguo
新的证据强调宿主微生物组对自身免疫性疾病（包括类风湿性关节炎（RA））发病机制的功能影响。然而，关于微生物生物分子尤其是微生物肽对调节免疫稳态的贡献的机制认识有限。在这里，通过挖掘扁桃体微生物组的宏基因组数据，发现了 RA 患者羊毛硫抗生素肽唾液霉素编码基因的缺陷，这与循环免疫细胞有很强的相关性。有证据表明，唾液霉素在抑制滤泡辅助性 T (Tfh) 细胞分化和白介素-21 (IL-21) 产生方面发挥免疫调节作用。机械上，唾液霉素直接结合并诱导IL-6和IL-21受体构象变化，从而抑制IL-6和IL-21与其受体的结合并抑制下游信号通路。最后，在 RA 小鼠模型中，salivaricin 给药对实验性关节炎发挥预防和治疗作用。总之，这些结果提供了微生物肽介导的免疫调节的机制联系。本研究发现，微生物组衍生的羊毛硫抗生素唾液霉素直接作用于 IL-6 和 IL-21 受体，抑制 Tfh 细胞的异常激活和 IL-21 的过度产生，从而维持宿主免疫稳态。类风湿性关节炎等自身免疫性疾病的扁桃体微生物组中唾液霉素的缺乏可能会降低适当调节免疫反应的能力，从而导致自身免疫性疾病。
Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin‐21 (IL‐21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL‐6 and IL‐21 receptors, thereby inhibiting the bindings of IL‐6 and IL‐21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides‐mediated immunomodulation. The present study uncovers that the microbiome‐derived lantibiotics salivaricins directly act on IL‐6 and IL‐21 receptors and suppress the abnormal activation of Tfh cell and overproduction of IL‐21, thus maintaining host immune homeostasis. The deficiency of salivaricins in the tonsillar microbiome of autoimmune diseases like rheumatoid arthritis may reduce the capacity for proper modulation of immune responses, thereby underlying autoimmune disorders.
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DOI：
10.1126/science.aau5480
发表时间：
2020-05-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lazzaro BP;Zasloff M;Rolff J
通讯作者：
Rolff J
影响因子：
15.9
作者：
Abdollahi-Roodsaz, Shahla;Joosten, Leo A. B.;Van den Berg, Wim B.
通讯作者：
Van den Berg, Wim B.
影响因子：
4.4
作者：
Hyink, Otto;Wescombe, Philip A.;Tagg, John R.
通讯作者：
Tagg, John R.
影响因子：
32.4
作者：
He, Jing;Tsai, Louis M.;Yu, Di
通讯作者：
Yu, Di
DOI：
10.1126/science.1208421
发表时间：
2011-11-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harker JA;Lewis GM;Mack L;Zuniga EI
通讯作者：
Zuniga EI