Secretome from SH-SY5Y APPSwe cells trigger time-dependent CHME3 microglia activation phenotypes, ultimately leading to miR-21 exosome shuttling
Secretome from SH-SY5Y APPSwe cells trigger time-dependent CHME3 microglia activation phenotypes, ultimately leading to miR-21 exosome shuttling
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DOI：
10.1016/j.biochi.2018.05.015
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发表时间：
2018-12-01
期刊：
影响因子：
3.9
通讯作者：
Brites, Dora
中科院分区：
文献类型：
--
作者：
Fernandes, Adelaide;Ribeiro, Ana Rita;Brites, Dora
外泌体介导的细胞间通讯在阿尔茨海默病（AD）的发病机制中具有广泛的影响。然而，关于其“作案手法”的信息有限，因为它严重依赖于外来体货物、环境背景和靶细胞。因此，更彻底地了解来自不同细胞类型的外泌体作为AD背景下神经炎症介质的作用是为创新和有效治疗开辟途径的决定性步骤。在这项研究中，我们证明，与原始SH-SY 5 Y（SH）细胞相比，用APP（695）的瑞典突变体（SHSwe）转染的SH-SY 5 Y细胞显着表达增加的炎症标志物，以及更高的APP和A β（1-40）产量。虽然当与SHSwe细胞共培养时对细胞外APP和A β积累发挥早期清除作用，但人CHME 3小胶质细胞逐渐失去这种性质，并表达促炎基因（iNOS、IL-1 β、THF-a、MHC II类、IL-6）和促分解基因（IL-10和精氨酸酶1），同时还证明衰老相关的β-半乳糖苷酶活性增加。有趣的是，SHSwe分泌组对炎症相关miRNA（miR）-155，miR-146 a和miR-124的上调显示出时间依赖性，并且与其各自的靶点（SOCS-1，IRAK 1和C/EBP-α）负相关。我们报告说，小胶质细胞还内化从SHSwe细胞释放的外泌体，这些外泌体富含miR-155、miR-146 a、miR-124、miR-21和miR-125 b，并重现了原始细胞。此外，我们表明SSHW衍生的外泌体能够诱导THF-alpha，HMGB 1和S100 B促炎标志物的急性和延迟的小胶质细胞上调，其中仅在其衍生的外泌体上发现S100 B。最重要的是，我们的数据表明，miR-21是一种一致的生物标志物，不仅在SHSwe细胞及其释放的外泌体中发现，而且在受体CHME 3小胶质细胞和衍生的外泌体中也发现。这项工作有助于增加对AD中神经元-小胶质细胞通讯和外泌体介导的神经炎症的理解，同时突出了miR-21作为治疗干预的有希望的生物标志物/靶标。(C)2018由Elsevier B. V.出版
Exosome-mediated intercellular communication has been increasingly recognized as having a broad impact on Alzheimer's disease (AD) pathogenesis. Still, limited information exists regarding their "modus operandi", as it critically depends on exosomal cargo, environmental context and target cells. Therefore, a more thorough understanding of the role of exosomes from different cell types as mediators of neuroinflammation in AD context is a decisive step to open avenues for innovative and efficient therapies. In this study, we demonstrate that SH-SY5Y cells transfected with the Swedish mutant of APP(695) (SHSwe) remarkably express increased inflammatory markers, combined with higher APP and A beta(1-40) production, when compared to naive SH-SY5Y (SH) cells. Although exerting an early clearance effect on extracellular APP and A beta accumulation when in co-culture with SHSwe cells, human CHME3 microglia gradually lose such property, and express both pro-inflammatory (iNOS, IL-1 beta, THF-alpha, MHC class II, IL-6) and proresolving genes (IL-10 and Arginase 1), while also evidence increased senescence-associated beta-galactosidase activity. Interestingly, upregulation of inflammatory-associated miRNA (miR)-155, miR-146a and miR-124 by SHSwe secretome shows to be time-dependent and to inversely correlate with their respective targets (SOCS-1, IRAK1 and C/EBP-alpha). We report that microglia also internalize exosomes released from SHSwe cells, which are enriched in miR-155, miR-146a, miR-124, miR-21 and miR-125b and recapitulate the cells of origin. Furthermore, we show that SHSwe-derived exosomes are capable of inducing acute and delayed microglial upregulation of THF-alpha, HMGB1 and S100B pro-inflammatory markers, from which only S100B is found on their derived exosomes. Most importantly, our data reveal that miR-21 is a consistent biomarker that is found not only in SHSwe cells and in their released exosomes, but also in the recipient CHME3 microglia and derived exosomes. This work contributes to the increased understanding of neuron-microglia communication and exosome-mediated neuroinflammation in AD, while highlights miR-21 as a promising biomarker/target for therapeutic intervention. (C) 2018 Published by Elsevier B.V.