细胞外囊泡介导的免疫代谢串扰：炎症调节和代谢性疾病发病机制的研究进展

摘要(中文译文)

细胞外囊泡（EVs）——几乎所有细胞类型分泌的脂质双层包裹的纳米颗粒——已从被视为被动的细胞副产物转变为协调细胞间和器官间通讯的主动信号节点。然而，该领域的积累速度超过了其整合速度：数百个EV-货物-表型关联以孤立网络边的形式存在，其系统级架构仍定义不清。在此，我们提出将该网络作为一个可操作框架，基于三条可证伪的公理：（i）生物体的EV补体构成一个可通过供体细胞×靶组织×货物类别寻址的网络；（ii）货物组成以可定量预测的方式追踪供体细胞代谢状态；（iii）促炎与促消退囊泡输出之间的整合平衡——而非任何单一网络边——决定生物体代谢表型。本综述沿EV生成、免疫-代谢相互作用、疾病机制和转化应用这一链条组织，综合阐述该网络如何维持代谢稳态，以及其失调如何驱动代谢性炎症——即肥胖、2型糖尿病、代谢功能障碍相关脂肪性肝病和动脉粥样硬化背后的慢性低度炎症。我们剖析该囊泡组的两个互惠弧。来自M1/M2巨噬细胞、Th17和调节性T细胞、树突状细胞、NK细胞和中性粒细胞的极化特异性EVs向脂肪组织、肝脏和胰腺递送炎症性或保护性货物。来自脂肪细胞、肝细胞、骨骼肌细胞、胰腺β细胞和肠上皮细胞的EVs反过来重塑免疫微环境。疾病作为这些弧的网络级配置而出现，而非孤立的边失败。我们对每一主张应用四级因果框架，区分相关性证据与货物耗竭和生理剂量验证。目前仅miR-155、miR-122、miR-690和miR-33满足最高层级；大多数货物需要系统性实验升级才能进行治疗转化。我们进一步区分临床前与临床验证证据，并将植物来源纳米囊泡降级为方法学警示，鉴于不可重复的跨界主张。转化部分针对该框架评估基于EV的液体活检生物标志物、天然和工程化治疗性EVs以及间充质干细胞来源EVs。我们最后以基础性、因果性和转化性知识缺口的结构化目录收尾，并提出基于单EV多组学、追踪、多器官器官芯片平台和纵向人类队列的优先研究议程。

Abstract

Extracellular vesicles (EVs)-lipid bilayer-enclosed nanoparticles secreted by virtually all cell types-have shifted from being viewed as passive cellular byproducts to active signaling nodes orchestrating inter-cellular and inter-organ communication. Yet the field has accumulated faster than it has integrated: hundreds of EV-cargo-phenotype associations exist as isolated edges of a network whose system-level architecture remains poorly defined. Here we propose the as an operational framework for that network, resting on three falsifiable axioms: (i) the EV complement of an organism constitutes a network addressable by donor cell × target tissue × cargo class; (ii) cargo composition tracks donor-cell metabolic state in a quantitatively predictable way; and (iii) the integrated balance between pro-inflammatory and pro-resolving vesicle outputs - rather than any single edge - determines the organismal metabolic phenotype. Organized along the chain of EV generation, immune-metabolic interaction, disease mechanism, and translational application, the review synthesizes how this network sustains metabolic homeostasis and how its dysregulation drives metaflammation, the chronic low-grade inflammation underlying obesity, type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and atherosclerosis. We dissect two reciprocal arcs of this vesiculome. Polarization-specific EVs from M1/M2 macrophages, Th17 and regulatory T cells, dendritic cells, NK cells, and neutrophils deliver inflammatory or protective cargo to adipose tissue, liver, and pancreas. EVs from adipocytes, hepatocytes, skeletal myocytes, pancreatic β-cells, and intestinal epithelial cells reciprocally reshape the immune microenvironment. Disease arises as a network-level configuration of these arcs rather than as isolated edge failures. We apply a four-tier causality framework to every claim, distinguishing correlational evidence from cargo-depletion and physiological-dose validation. Only miR-155, miR-122, miR-690, and miR-33 currently satisfy the highest tier; most cargoes require systematic experimental escalation before therapeutic translation. We further separate preclinical from clinically validated evidence, and downgrade plant-derived nanovesicles to a methodological cautionary note given non-reproducible cross-kingdom claims. The translational arm evaluates EV-based liquid biopsy biomarkers, native and engineered therapeutic EVs, and mesenchymal stem cell-derived EVs against this framework. We close with a structured catalogue of foundational, causal, and translational knowledge gaps and a priority research agenda built on single-EV multi-omics, tracking, multi-organ organoid-on-chip platforms, and longitudinal human cohorts.

如何引用

Frontiers in immunology 的其他文献

• 胎儿生长受限和子痫前期共有的糖基化相关分子机制和免疫浸润模式
• 天然多糖作为代谢性疾病中的免疫代谢调节剂：机制与转化挑战
• CTLA-4在干燥综合征中的作用和功能
• 心力衰竭及其进展与心外膜脂肪组织中淋巴细胞谱的变化有关
• 人工智能驱动的暴露组与多组学整合在肝癌生物标志物发现中的应用：文献综述
• 人干扰素-ω：一种被低估的I型干扰素
• 肝脏sEH通过IL-6和肝-脑轴驱动应激诱导的神经炎症
• HPV阳性口咽癌中与淋巴结状态相关的空间免疫程序在淋巴滤泡区域和瘤周扁桃体组织之间存在差异
• 单细胞分辨率下解码良性前列腺增生：异质性、炎症及雄激素驱动发病机制之外的探索
• 有氧运动联合FK866改善NAMPT异常的APP/PS1小鼠的阿尔茨海默病样病理