Small Extracellular Vesicles Containing miR-381-3p from Keratinocytes Promote T Helper Type 1 and T Helper Type 17 Polarization in Psoriasis
Small Extracellular Vesicles Containing miR-381-3p from Keratinocytes Promote T Helper Type 1 and T Helper Type 17 Polarization in Psoriasis
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含有来自角质形成细胞的 miR-381-3p 的小细胞外囊泡促进银屑病中 THelper 1 型和 T Helper 17 型极化
DOI：
10.1016/j.jid.2020.07.009
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发表时间：
2021-02-19
影响因子：
6.5
通讯作者：
Wang, Gang
中科院分区：
文献类型：
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作者：
Jiang, Man;Fang, Hui;Wang, Gang
辅助性T细胞在银屑病发病机制中起着至关重要的作用。T细胞和银屑病角质形成细胞（KCs）之间的通讯有助于驱动Th 1和Th 17应答，但其潜在机制尚不清楚。小细胞外囊泡（sEV）是细胞间通讯的新兴介质。在这里，我们研究了KC衍生的sEV在银屑病Th 1和Th 17应答中的作用。我们在正常（未治疗）和银屑病（阿托伐他汀治疗）条件下从KC中分离和鉴定sEV。两种条件下的sEV均表现出杯状形态并表达标志物CD 63和CD 81。CD 4（+）T细胞可以摄取经苦参碱处理的KC的sEV，导致Th 1和Th 17极化的诱导。小RNA测序显示，miR-381- 3 p在马槟榔处理的KC的sEV和银屑病患者的CD 4（+）T细胞中显著增加。此外，含有sEV的miR-381- 3 p负责sEV诱导的Th 1和Th 17极化。我们进一步发现，miR-381- 3 p靶向E3泛素连接酶UBR 5的3'非翻译区并稳定ROR γ t蛋白表达。它还靶向与激活的T-bet和ROR γ t转录相关的FOXO 1的3'非翻译区。综上所述，我们认为银屑病KCs通过sEVs将miR-381- 3 p转移到CD 4（+）T细胞，诱导Th 1和Th 17极化，促进银屑病的发展。我们的研究结果激励了未来对KC衍生的sEV或其特定货物作为银屑病治疗候选物的研究。
T helper cells are crucial for psoriasis pathogenesis. Communication between T cells and psoriatic keratinocytes (KCs) helps drive the Th1 and Th17 response, but the underlying mechanism is not well-understood. Small extracellular vesicles (sEVs) are emerging mediators of intercellular communication. Here, we investigated the role of KC-derived sEVs in the Th1 and Th17 response in psoriasis. We isolated and characterized sEVs from KCs under normal (untreated) and psoriatic (cytokine-treated) conditions. sEVs under both conditions exhibited a cup-shaped morphology and expressed markers CD63 and CD81. sEVs from cytokine-treated KCs can be taken up by CD4(+)T cells, leading to the induction of Th1 and Th17 polarization. Small RNA sequencing revealed that miR-381-3p was significantly increased in sEVs from cytokine-treated KCs and in CD4(+)T cells from patients with psoriasis. Moreover, sEVs-containing miR-381-3p was responsible for sEVs-induced Th1 and Th17 polarization. We further found that the miR-381-3p targeted to the 3' untranslated region of E3 ubiquitin-ligase UBR5 and stabilized ROR gamma t protein expression. It also targeted to the 3' untranslated region of FOXO1, associated with activated T-bet and ROR gamma t transcription. Taken together, we propose that psoriatic KCs transfer miR-381-3p to CD4(+)T cells through sEVs, inducing Th1 and Th17 polarization and promoting psoriasis development. Our findings motivate future studies of KC-derived sEVs or their specific cargoes as therapeutic candidates for psoriasis.