Nature:Akk菌如何调节免疫?锁定新的关键分子
创作:mildbreeze 审核:mildbreeze 08月01日
  • 通过一系列生物化学和分子生物学方法,研究Akk菌中具有免疫调节功能的分子;
  • 发现Akk菌的细胞膜磷脂a15:0-i15:0 PE(一种含2个支链的二酰基磷脂酰乙醇胺)能诱导树突状细胞释放TNFα和IL-6;
  • 构效分析表明,a15:0-i15:0 PE的免疫原性依赖其结构特征,并需要其与TLR2和TLR1结合形成TLR2-TLR1异二聚体;
  • a15:0-i15:0 PE诱导细胞因子的能力逊于LPS等TLR2激动剂,且只诱导特定的促炎细胞因子;
  • 低剂量的a15:0-i15:0 PE可重置树突状细胞的活化阈值,降低对后续免疫刺激(如LPS)的反应,这可能部分解释了Akk菌的免疫调节作用。
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mildbreeze
肠道菌群中的嗜黏蛋白阿克曼菌(Akk菌)可谓是一种“明星”肠菌,可发挥多种健康益处,包括调节宿主免疫,然而其分子机制仍待揭示。Nature最新发表了来自哈佛医学院Jon Clardy团队和Ramnik Xavier团队的合作研究,通过一系列体外实验,鉴定出Akk菌表达的一种具有免疫调节作用的磷脂分子,并揭示了其功能特征和机制。研究表明,该分子通过作用于非经典的TLR2-TLR1异二聚体来引起特定炎症细胞因子的释放,且在低剂量作用下能“钝化”免疫细胞的活化阈值。这为Akk菌的免疫调节作用提供了一种新的分子机制,将菌、效应分子、信号途径和生物学表型串联起来。这些发现仍需在体内模型中进行验证,但其采用的研究方法和思路对于挖掘其他肠道微生物的分子机制具有参考意义。
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Nature [IF:69.504]

Akkermansia muciniphila phospholipid induces homeostatic immune responses

嗜黏蛋白阿克曼菌磷脂诱导稳态免疫反应

10.1038/s41586-022-04985-7

07-27, Article

Abstract & Authors:展开

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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.

First Authors:
Munhyung Bae,Chelsi D Cassilly

Correspondence Authors:
Ramnik J Xavier,Jon Clardy

All Authors:
Munhyung Bae,Chelsi D Cassilly,Xiaoxi Liu,Sung-Moo Park,Betsabeh Khoramian Tusi,Xiangjun Chen,Jaeyoung Kwon,Pavel Filipčík,Andrew S Bolze,Zehua Liu,Hera Vlamakis,Daniel B Graham,Sara J Buhrlage,Ramnik J Xavier,Jon Clardy

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