Wasson, Christopher W;
Dibb, Sophie L;
Caballero-Ruiz, Begoña;
Bamigbola, Ifeoluwa E;
Di Donato, Stefano;
Madourie-Clavane, Eva M;
Wells, Rebecca;
... Del Galdo, Francesco; + view all
(2025)
Transforming growth factor beta (TGF-β) induces type 1 interferon signalling in systemic sclerosis keratinocytes through the chloride intracellular channel 4 (CLIC4).
Arthritis Res Ther
, 27
, Article 173. 10.1186/s13075-025-03632-6.
Preview |
Text
Denton_s13075-025-03632-6.pdf Download (5MB) | Preview |
Abstract
OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease, which is characterized by fibrosis of the skin, progressing to affect the internal organs in the most serve cases. Type 1 interferon (IFN) signalling plays a major role in SSc disease progression. The cytokine TGF-β has been extensively shown to be a major driver of fibrosis but its role in the induction of the type 1 interferon response is poorly understood. METHODS: Type 1 IFN signalling was activated in keratinocytes using a range of agonists, IFN2α, Poly I:C, Poly dA:dT, LPS and TGF-β. CLIC4 activity was inhibited with the small molecule chloride channel inhibitors NPPB, IAA:94 and siRNA specific to CLIC4. Conditioned media collected from Healthy and SSc dermal fibroblasts was used to stimulate keratinocytes. RESULTS: TGF-β stimulation induces a type 1 IFN response in keratinocytes, dependent on the chloride intracellular channel 4 (CLIC4). Inhibition of CLIC4 via small molecule inhibitors or siRNA attenuates TGF-β mediated activation of Signal Transducer and Activator of Transcription 1 (STAT1) in keratinocytes. Further analysis revealed SSc dermal fibroblasts induce a type 1 IFN response in keratinocytes in part through a TGFβR1-CLIC4 axis. CONCLUSIONS: This study shows the ability of CLIC4 to enhance TGF-β signalling is essential for aberrant type 1 interferon signalling in SSc skin.
| Type: | Article |
|---|---|
| Title: | Transforming growth factor beta (TGF-β) induces type 1 interferon signalling in systemic sclerosis keratinocytes through the chloride intracellular channel 4 (CLIC4) |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13075-025-03632-6 |
| Publisher version: | https://doi.org/10.1186/s13075-025-03632-6 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Scleroderma, Interferon, CLIC4, STAT1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213110 |
Archive Staff Only
 |
View Item |
