Peng Xin, Hou Lei, Wu Xue, Liu Zhengqi, Wang Yun, Zeng Ping, Yang Ying, Ma Wukai, Yang Peng
Guizhou University of Traditional Chinese Medicine, Guiyang, 550002, China.
Department of Rheumatology and Immunology, Guizhou Provincial Traditional Chinese and Western Medicine Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, China.
J Mol Med (Berl). 2023 Oct;101(10):1289-1304. doi: 10.1007/s00109-023-02361-0. Epub 2023 Sep 1.
Primary Sjögren's syndrome (pSS) is an autoimmune disease represented by exocrine gland epithelial cell lesions. However, the mechanism underlying these lesions remains unclear. This study analyzed the plasma exosomes of pSS patients using proteomics and revealed the presence of 24 differentially expressed proteins (DEPs) involved in the primary biological processes and signaling pathways related to ferroptosis. The DEPs enriched in the ferroptosis-related items were represented by downregulated ceruloplasmin (CP) and transferrin (TF). CC analysis of GO enrichment showed that CP and TF were localized at the apical plasma membrane, which is currently found only in epithelial cells. PPI analysis indicated that these exosomal DEPs formed a clustering network containing CP and TF. Among them, C5, C9, Haptoglobin (HP), and SERPING1 interacted directly with CP and TF. Notably, the expression of these proteins significantly decreased in both the pSS and secondary Sjögren's syndrome (sSS) plasma exosomes but not in non-autoimmune sicca syndrome (nSS). In addition, their expression levels were significantly different in the exosomes and plasma. More importantly, the plasma and salivary exosomes of pSS patients contain higher levels of exocrine gland epithelial autoantigens SSA and SSB than those of healthy controls, and epithelial cells with positive labial glands biopsy (LGB) were more susceptible to ferroptosis than those with negative LGB. The results indicated that ferroptosis may be closely related to SS epithelial cell lesions. KEY MESSAGES: • pSS plasma exosomes contain epithelial cell-derived proteins involved in ferroptosis. • Complement C5 and C9 may be new molecules involved in ferroptosis and play a crucial role in pSS epithelial cell pathology. • The serum exosomes from pSS patients, not nSS patients, contain ferroptosis-related proteins. • The changes in the ferroptosis-related protein content in the exosomes can better reflect the state of the epithelial cell lesions than those in the plasma.
原发性干燥综合征（pSS）是一种以外分泌腺上皮细胞病变为特征的自身免疫性疾病。然而，这些病变背后的机制仍不清楚。本研究利用蛋白质组学分析了pSS患者的血浆外泌体，发现了24种差异表达蛋白（DEP），这些蛋白参与了与铁死亡相关的主要生物学过程和信号通路。在与铁死亡相关项目中富集的DEP以铜蓝蛋白（CP）和转铁蛋白（TF）的下调为代表。GO富集的CC分析表明，CP和TF定位于顶端质膜，目前仅在上皮细胞中发现。PPI分析表明，这些外泌体DEP形成了一个包含CP和TF的聚类网络。其中，C5、C9、触珠蛋白（HP）和丝氨酸蛋白酶抑制剂C1酯酶抑制因子（SERPING1）直接与CP和TF相互作用。值得注意的是，这些蛋白的表达在pSS和继发性干燥综合征（sSS）的血浆外泌体中均显著降低，但在非自身免疫性干燥综合征（nSS）中未降低。此外，它们在外泌体和血浆中的表达水平存在显著差异。更重要的是，pSS患者的血浆和唾液外泌体中所含的外分泌腺上皮自身抗原SSA和SSB水平高于健康对照，唇腺活检（LGB）阳性的上皮细胞比LGB阴性的上皮细胞更容易发生铁死亡。结果表明，铁死亡可能与SS上皮细胞病变密切相关。关键信息：• pSS血浆外泌体含有参与铁死亡的上皮细胞衍生蛋白。• 补体C5和C9可能是参与铁死亡的新分子，在pSS上皮细胞病理中起关键作用。• pSS患者而非nSS患者的血清外泌体含有与铁死亡相关的蛋白。• 外泌体中铁死亡相关蛋白含量的变化比血浆中的变化能更好地反映上皮细胞病变状态。
