PO.IM01.04 · 免疫学
人血清蛋白质组学揭示电子烟使用者中细胞外囊泡介导的代谢-黏附信号传导及适应性免疫抑制
Human serum proteomics reveals extracellular vesicle-mediated metabolic-adhesive signaling and suppression of adaptive immunity in E-cigarette users
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摘要 Abstract
中文摘要
背景：虽然可燃性香烟烟雾的毒理学影响已得到充分表征，但电子烟使用的全身生物学后果仍知之甚少。由于血清含有分泌型和囊泡相关蛋白，它提供了一个观察对吸电子烟早期生物学应答的窗口。我们进行了血清蛋白质组学，以确定吸电子烟如何塑造细胞外囊泡（EV）的生物学、代谢应激通路和人类免疫功能。
方法：对成人电子烟使用者和非吸电子烟对照者的血清进行LC-MS/MS蛋白质组学分析，随后在GO生物过程（BP）、细胞组分（CC）、分子功能（MF）、KEGG以及经过整理的MSigDB C2分泌组/EV特征集中进行基因集富集分析（GSEA）。
结果：我们的结果表明，来自人类吸电子烟者的血清显示糖酵解和氧化应激适应性酶（GPI、PKM、IDH1、SOD2）表达增加，同时缺氧上调蛋白1（HYOU1）显著上调，表明参与了缺氧应答/ER应激代谢程序。与此一致，GSEA揭示了糖酵解、碳代谢、核糖核苷代谢和前体代谢物生成的富集。细胞组分分析确定了细胞外囊泡、分泌囊泡、膜封闭腔和经整理的分泌组特征集的强富集，并伴随ECM-细胞骨架重塑通路的上调，包括黏着斑、ECM-受体相互作用和肌动蛋白丝组织。这些EV相关通路得到EV相关黏附分子和免疫调节因子丰度增加的支持，包括神经细胞黏附分子L1样蛋白（CHL1）以及整合素ITGB1和ITGB2，已知它们在上皮或免疫应激期间被包装进EV中。与此同时，免疫相关通路（包括适应性免疫应答、免疫球蛋白介导的免疫和抗原结合）是唯一负富集的过程，表明体液免疫受到选择性抑制。
结论：慢性电子烟使用诱导一种协调的血清表型，其特征为缺氧/ER应激诱导的代谢重编程、细胞外囊泡和黏附信号增强以及适应性免疫机制下调。这些发现提示，代谢应激驱动的EV分泌可能有助于电子烟使用者中免疫通讯的改变和抗体介导应答的减弱。
查看英文原文 English abstract
Background: While the toxicological impact of combustible cigarette smoke is well characterized, the systemic biological consequences of electronic cigarette use remain poorly understood. As serum contains secreted and vesicle-associated proteins, it provides a window into early biological responses to vaping. We performed serum proteomics to determine how vaping shapes the biology of extracellular vesicles (EVs), metabolic stress pathways, and immune function in humans.
Methods: Serum from adult e-cigarette users and non-vaper controls underwent LC-MS/MS proteomics followed by Gene Set Enrichment Analysis (GSEA) across GO Biological Process (BP), Cellular Component (CC), Molecular Function (MF), KEGG, and curated MSigDB C2 secretome/EV signatures.
Results: Our results demonstrate that serum from human vapers showed increased expression of glycolytic and oxidative stress-adaptive enzymes (GPI, PKM, IDH1, SOD2), along with significant upregulation of Hypoxia up-regulated protein 1 (HYOU1), indicating engagement of a hypoxia-responsive/ER stress metabolic program. Concordantly, GSEA revealed enrichment of glycolysis, carbon metabolism, ribonucleoside metabolism, and precursor metabolite generation. Cellular component analysis identified strong enrichment of extracellular vesicle, secretory vesicle, membrane-enclosed lumen, and curated secretome signatures, accompanied by upregulation of ECM-cytoskeletal remodeling pathways, including focal adhesion, ECM-receptor interaction, and actin filament organization. These EV-linked pathways were supported by increased abundance of EV-associated adhesion molecules and immunomodulatory factors, including the Neural cell adhesion molecule L1-like protein (CHL1) and the integrins ITGB1 and ITGB2 , which are known to be packaged into EVs during epithelial or immune stress. In parallel, immune-related pathways, including adaptive immune response, immunoglobulin-mediated immunity, and antigen binding, were the only processes negatively enriched, indicating selective suppression of humoral immunity.
Conclusions: Chronic e-cigarette use induces a coordinated serum phenotype characterized by hypoxia/ER stress-induced metabolic reprogramming, enhanced extracellular vesicle and adhesion signaling, and downregulation of adaptive immune mechanisms. These findings suggest that metabolic stress-driven EV secretion may contribute to altered immune communication and weakened antibody-mediated responses in e-cigarette users.
利益披露 Disclosure
R. Begum, None.