Exosomal Transport of Hepatocyte-Derived Drug-Modified Proteins to the Immune System.
Exosomal Transport of Hepatocyte-Derived Drug-Modified Proteins to the Immune System.
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肝细胞源性药物修饰蛋白的外泌体转运至免疫系统。
DOI：
10.1002/hep.30701
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Ogese MO
中科院分区：
文献类型：
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作者：
Ogese MO
特异质药物性肝损伤（DILI）是一种罕见的、通常难以预测的不良反应，具有复杂的病理机制。然而，现在很明显，某些形式的DILI是免疫介导的，可能涉及药物特异性T细胞的活化。外泌体是细胞衍生的囊泡，其将RNA、脂质和蛋白质货物从其来源细胞携带到远处细胞，并且它们可能在免疫激活中发挥作用。在此，用与DILI高发生率相关的药物（氟氯西林、阿莫西林、异烟肼和亚硝基磺胺甲恶唑）处理原代人肝细胞，以表征包装在外来体内的蛋白质，这些蛋白质随后转运至树突细胞进行处理。外泌体在50和100 nm之间测量，并表达富集的CD 63。液相色谱-串联质谱（LC/MS-MS）鉴定了2，109种蛋白质，其中608种蛋白质在所有外泌体样品中被定量。数据可通过ProteomeXchange获得，标识符为PXD 010760。对基因本体的分析表明，无论药物治疗如何，外来体都反映了整个人类肝脏组织中存在的蛋白质家族。然而，来自亚硝基磺胺甲恶唑处理的肝细胞的外泌体选择性地包装了特定的蛋白质子集。LC/MS-MS还显示存在用阿莫西林、氟氯西林和亚硝基磺胺甲恶唑共价修饰的肝细胞源性外泌体蛋白。单核细胞来源的树突状细胞对外泌体的摄取沉默发生，主要通过吞噬作用，并被latrunculin A抑制。阿莫西林修饰的9-mer肽来源于外泌体转录因子蛋白SRY（性别决定区Y）-box 30激活来自人类白细胞抗原A*02：01阳性人类供体的幼稚T细胞。结论：本研究表明外泌体具有将药物特异性肝细胞源性信号传递给免疫系统的潜力，并为诱导药物半抗原特异性T细胞应答提供了途径。
Idiosyncratic drug‐induced liver injury (DILI) is a rare, often difficult‐to‐predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune‐mediated and may involve the activation of drug‐specific T cells. Exosomes are cell‐derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso‐sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography–tandem mass spectrometry (LC/MS‐MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso‐sulfamethoxazole‐treated hepatocytes selectively packaged a specific subset of proteins. LC/MS‐MS also revealed the presence of hepatocyte‐derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso‐sulfamethoxazole. Uptake of exosomes by monocyte‐derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin‐modified 9‐mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)‐box 30 activated naïve T cells from human leukocyte antigen A*02:01–positive human donors.Conclusion:This study shows that exosomes have the potential to transmit drug‐specific hepatocyte‐derived signals to the immune system and provide a pathway for the induction of drug hapten‐specific T‐cell responses.