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Updated: Sep 9, 2025

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Transforming growth factor beta (TGF-β) induces type 1 interferon signalling in systemic sclerosis keratinocytes
Christopher W Wasson1, Sophie L Dibb2, Begoña Caballero-Ruiz2
1Faculty of Medicine and Health, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK. c.w.wasson@leeds.ac.uk.
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.
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