Plasma exosomal miR-375-3p regulates mitochondria-dependent keratinocyte apoptosis by targeting XIAP in severe drug-induced skin reactions
Plasma exosomal miR-375-3p regulates mitochondria-dependent keratinocyte apoptosis by targeting XIAP in severe drug-induced skin reactions
复制标题
严重药物引起的皮肤反应中血浆外泌体 miR-375-3p 通过靶向 XIAP 调节线粒体依赖性角质形成细胞凋亡
DOI：
10.1126/scitranslmed.aaw6142
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Fu M
中科院分区：
文献类型：
--
作者：
Zhang C;Zhu Z;Gao J;Yang L;Dang E;Fang H;Shao S;Zhang S;Xiao C;Yuan X;Li W;Abe R;Qiao H;Wang G;Fu M
在Stevens-Johnson综合征和中毒性表皮坏死松解症中，循环外体miR-375-3p通过XIAP抑制促进角质形成细胞的凋亡。严重的外周体史蒂文斯-约翰逊综合征(SJS)和中毒性表皮坏死松解症(TEN)是严重的、潜在致命的药物引起的皮肤反应，导致皮肤死亡和脱落。张某等人。表明SJS/TEN患者的血浆外切体进入并促进原代人角质形成细胞的凋亡。他们发现miR-375-3p在患者来源的外体中含量丰富，并与临床严重程度相关，并进一步表明这种microRNA通过靶向凋亡抑制物XIAP而诱导角质形成细胞死亡。这项工作揭示了严重皮肤病的病因学，并展示了细胞外小泡及其货物如何改变疾病生理。Stevens-Johnson综合征(SJS)和中毒性表皮坏死松解症(TEN)是以角质形成细胞凋亡为特征的药物所致的严重皮肤反应。外切体是体液中的纳米大小的膜性囊泡。它们含有功能蛋白、mRNAs和miRNAs，它们会导致免疫功能障碍并影响疾病的进展。然而，它们在SJS/TEN中的作用和机制仍不清楚。我们的结果表明，从SJS/TEN患者血浆中分离到的外切体直径为30~200 nm，表达CD9、CD63、CD81和TSG101外切体标记蛋白。MIR-375-3p在35例SJS/TEN患者中表达明显上调，并与临床严重程度相关。体外培养的人原代角质形成细胞可内化血浆外切体，促进角质形成细胞的凋亡。此外，miR-375-3p的过表达通过下调X连锁的凋亡抑制蛋白(XIAP)促进了人原代角质形成细胞的固有(线粒体依赖)凋亡。XIAP是原代角质形成细胞中的关键凋亡调节因子。综上所述，我们的研究表明，在SJS/TEN患者中，循环外体miR-375-3p进入角质形成细胞，下调XIAP，并诱导角质形成细胞凋亡。
Circulating exosomal miR-375-3p promotes keratinocyte apoptosis via XIAP repression in Stevens-Johnson syndrome and toxic epidermal necrolysis. Excoriating exosomes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe, potentially deadly drug-induced cutaneous reactions that result in skin death and detachment. Zhang et al. show that plasma exosomes from patients with SJS/TEN entered and promoted the apoptosis of primary human keratinocytes. They found that miR-375-3p was abundant in the patient-derived exosomes and correlated with clinical severity, and further showed that this microRNA induced keratinocyte cell death by targeting the apoptosis inhibitor XIAP. This work sheds light on the etiology of a serious skin condition and demonstrates how extracellular vesicles and their cargo can modify disease physiology. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions characterized by keratinocyte apoptosis. Exosomes are nanometer-sized membranous vesicles in body fluids. They contain functional proteins, mRNAs, and miRNAs, which induce immune dysfunction and influence disease progression. However, their roles and mechanisms in SJS/TEN remain unknown. Our results demonstrate that exosomes isolated from the plasma of patients with SJS/TEN were 30 to 200 nm in diameter and expressed CD9, CD63, CD81, and TSG101 exosome marker proteins. miR-375-3p was markedly up-regulated in 35 patients with SJS/TEN and correlated with clinical severity. Plasma exosomes were internalized by human primary keratinocytes and promoted keratinocyte apoptosis in vitro. Furthermore, miR-375-3p overexpression promoted intrinsic (mitochondria-dependent) apoptosis of human primary keratinocytes via down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a key apoptosis regulator in primary human keratinocytes. In sum, our study indicates that the circulating exosomal miR-375-3p enters keratinocytes, down-regulates XIAP, and induces keratinocyte apoptosis in patients with SJS/TEN.
登录
查看更多内容
DOI：
10.1111/1440-1681.13047
发表时间：
2019-02-01
影响因子：
2.9
作者：
Guo, Feng;Gao, Yongjian;Jin, Chunxiang
通讯作者：
Jin, Chunxiang
影响因子：
12.4
作者：
Hamacher-Brady, A.;Choe, S. C.;Brady, N. R.
通讯作者：
Brady, N. R.
影响因子：
2.9
作者：
Li, Lina;Jia, Liping;Ding, Yan
通讯作者：
Ding, Yan
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
K. Livak;Thomas D. Schmittgen
通讯作者：
K. Livak;Thomas D. Schmittgen
影响因子：
6.5
作者：
Bastuji-Garin, S;Fouchard, N;Wolkenstein, P
通讯作者：
Wolkenstein, P