Bryon, J., Wasson, C.W. orcid.org/0000-0001-6558-4738, Koeppen, K. et al. (7 more authors) (2024) Systemic Sclerosis dermal fibroblast exosomes trigger a Type 1 interferon response in keratinocytes through the TBK/JAK/STAT signalling axis. Arthritis & Rheumatology. ISSN 2326-5191
Abstract
Background
Activation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. 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 healthy and SSc patients’ forearms 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 analysed by 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 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 upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation 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 indicates that SSc fibroblasts exosomes contributes to the Type I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is the peer reviewed version of the following article: Bryon, J., Wasson, C.W., Koeppen, K., Chandler, F., Willis, L.F., Di Donato, S., Klein, E., Zeqiraj, E., Ross, R.L. and Del Galdo, F. (2024), Systemic Sclerosis dermal fibroblast exosomes trigger a Type 1 interferon response in keratinocytes through the TBK/JAK/STAT signalling axis. Arthritis Rheumatol. Accepted Author Manuscript. https://doi.org/10.1002/art.43029, which has been published in final form at https://doi.org/10.1002/art.43029. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 22 Oct 2024 09:17 |
Last Modified: | 22 Oct 2024 09:17 |
Published Version: | https://acrjournals.onlinelibrary.wiley.com/doi/10... |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/art.43029 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:218709 |
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