Systemic Sclerosis Dermal Fibroblast Exosomes Trigger Type 1 Interferon Responses in Keratinocytes via a TBK/JAK/STAT Signaling Axis

IF 11.4 1区 医学 Q1 RHEUMATOLOGY Arthritis & Rheumatology Pub Date : 2024-10-16 DOI:10.1002/art.43029
Jessica Bryon, Christopher W. Wasson, Katja Koeppen, Francesca Chandler, Leon F. Willis, Stefano Di Donato, Elliott Klein, Elton Zeqiraj, Rebecca L. Ross, Francesco Del Galdo
{"title":"Systemic Sclerosis Dermal Fibroblast Exosomes Trigger Type 1 Interferon Responses in Keratinocytes via a TBK/JAK/STAT Signaling Axis","authors":"Jessica Bryon,&nbsp;Christopher W. Wasson,&nbsp;Katja Koeppen,&nbsp;Francesca Chandler,&nbsp;Leon F. Willis,&nbsp;Stefano Di Donato,&nbsp;Elliott Klein,&nbsp;Elton Zeqiraj,&nbsp;Rebecca L. Ross,&nbsp;Francesco Del Galdo","doi":"10.1002/art.43029","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>Activation of type I interferon (IFN) response has been shown to correlate with disease activity in systemic sclerosis (SSc). It is currently unknown whether the tissue-specific type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages in vitro. Here, we aimed to determine the source of type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Skin biopsies were obtained from the forearms of healthy patients and of those with SSc and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analyzed by RNA sequencing (RNA-seq) analysis. TANK-binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and tofacitinib, respectively.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>SSc skin biopsies showed the highest levels of type I IFN response in the epidermal layer. RNA-seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong up-regulation of IFN signature genes induced by SSc exosomes compared to healthy control. Inhibition of TBK or JAK activity suppressed the up-regulation of the IFN signature induced by SSc exosomes.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>IFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicate that SSc fibroblast exosomes contribute to the type I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.</p>\n </section>\n </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"77 3","pages":"322-334"},"PeriodicalIF":11.4000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.43029","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/art.43029","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Objective

Activation of type I interferon (IFN) response has been shown to correlate with disease activity in systemic sclerosis (SSc). It is currently unknown whether the tissue-specific type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages in vitro. Here, we aimed to determine the source of type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.

Methods

Skin biopsies were obtained from the forearms of healthy patients and of those with SSc and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analyzed by RNA sequencing (RNA-seq) analysis. TANK-binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and tofacitinib, respectively.

Results

SSc skin biopsies showed the highest levels of type I IFN response in the epidermal layer. RNA-seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong up-regulation of IFN signature genes induced by SSc exosomes compared to healthy control. Inhibition of TBK or JAK activity suppressed the up-regulation of the IFN signature induced by SSc exosomes.

Conclusion

IFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicate that SSc fibroblast exosomes contribute to the type I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
系统性硬化症真皮成纤维细胞外泌体通过 TBK/JAK/STAT 信号轴触发角质形成细胞的 1 型干扰素反应
背景I型IFN反应的激活已被证明与系统性硬化症的疾病活动有关。目前尚不清楚组织特异性 I 型 IFN 激活是血液中观察到的反应的结果还是其来源。最近有研究表明,来自 SSc 成纤维细胞的外泌体可在体外激活巨噬细胞。在此,我们旨在确定 SSc 皮肤活检组织中 I 型 IFN 特征的来源,以及 SSc 皮肤成纤维细胞的外泌体在这一过程中的潜在作用。通过超速离心从健康和 SSc 皮肤成纤维细胞上清液中分离出外泌体,并将其添加到人类皮肤角质细胞中。通过RNA-seq分析对角质细胞转录组进行了分析。分别使用小分子抑制剂(GSK8612)和托法替尼抑制 TANK 结合激酶(TBK)和 JAK。与健康对照组相比,暴露于真皮成纤维细胞外泌体后的角朊细胞转录组的RNA-seq分析表明,SSc外泌体诱导的IFN特征基因有很强的上调。结论IFN对SSc角质形成细胞的激活依赖于它们与真皮成纤维细胞的串联,并可由细胞外的外泌体诱导。我们的数据表明,SSc成纤维细胞外泌体通过激活TBK上游的模式识别受体,促进了SSc皮肤中I型IFN的激活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Arthritis & Rheumatology
Arthritis & Rheumatology RHEUMATOLOGY-
CiteScore
20.90
自引率
3.00%
发文量
371
期刊介绍: Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.
期刊最新文献
Association of thigh intramuscular fat infiltration with incident knee and hip osteoarthritis: a longitudinal cohort study Beyond Joint Pain – Expanding Insights on the Impact of Nonarticular Pain in Early Rheumatoid Arthritis Penetrating aortic ulceration as a initial presentation of Erdheim-Chester Disease Notes from the field: The Inflation Reduction Act and Enbrel Sex Differences in B Cells from the Joints of Children with Oligoarticular Juvenile Idiopathic Arthritis
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1