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Akkermansia muciniphila phospholipid induces homeostatic immune responses
Nature ( IF 50.5 ) Pub Date : 2022-07-27 , DOI: 10.1038/s41586-022-04985-7
Munhyung Bae 1, 2 , Chelsi D Cassilly 1 , Xiaoxi Liu 1, 3 , Sung-Moo Park 4, 5, 6 , Betsabeh Khoramian Tusi 4, 5, 6 , Xiangjun Chen 4, 5, 6 , Jaeyoung Kwon 1, 7 , Pavel Filipčík 8, 9 , Andrew S Bolze 4 , Zehua Liu 4 , Hera Vlamakis 4 , Daniel B Graham 4, 5, 6 , Sara J Buhrlage 1, 3 , Ramnik J Xavier 4, 5, 6 , Jon Clardy 1
Affiliation  

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1,2,3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4,5,6,7. Here we report the identification of a lipid from A. muciniphila’s cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure–activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2–TLR1 heterodimer9,10. Certain features of the phospholipid’s activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2–TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila’s ability to set immunological tone and its varied roles in health and disease.



中文翻译:

阿克曼氏菌磷脂诱导稳态免疫反应

多项研究已经建立了人类肠道细菌与宿主生理学之间的关联,但确定这些关联背后的分子机制一直具有挑战性1,2,3Akkermansia muciniphila与宿主代谢的积极全身效应、癌症免疫治疗中检查点阻断的有利结果以及稳态免疫密切相关4,5,6,7在此,我们报告了从A. muciniphila细胞膜中鉴定出的脂质,该脂质概括了A. muciniphila在细胞测定中的免疫调节活性8。分离的免疫原是一种具有两个支链的二酰基磷脂酰乙醇胺 (a15:0-i15:0 PE),通过光谱分析和化学合成进行了表征。a15:0-i15:0 PE 的免疫原活性具有高度受限的结构-活性关系,其免疫信号传导需要意想不到的 Toll 样受体 TLR2–TLR1 异二聚体9,10。磷脂活性的某些特征值得注意:它的效力明显低于已知的天然和合成 TLR2 激动剂;它优先诱导一些炎症细胞因子,但不诱导其他细胞因子;并且,在低剂量(EC 50的 1% )时,它会重置免疫信号的激活阈值和反应。鉴定该分子和等效合成类似物、其非典型 TLR2-TLR1 信号通路、其免疫调节选择性及其低剂量免疫调节作用,为 A. muciniphila 设定免疫调节及其能力的模型提供了分子机制。在健康和疾病中发挥不同的作用。

更新日期:2022-07-28
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