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Objectives <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>This study shows the ability of CLIC4 to enhance TGF-β signalling is essential for aberrant type 1 interferon signalling in SSc skin.</p>

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Transforming growth factor beta (TGF-β) induces type 1 interferon signalling in systemic sclerosis keratinocytes through the chloride intracellular channel 4 (CLIC4)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月1日

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  • Christopher W. Wasson,
  • Sophie L. Dibb,
  • Begoña Caballero-Ruiz,
  • Ifeoluwa E. Bamigbola,
  • Stefano Di Donato,
  • Eva M. Madourie-Clavane,
  • Rebecca Wells,
  • Vishal Kakkar,
  • Enrico De Lorenzis,
  • Jessica Bryon,
  • Emma Derrett-Smith,
  • Christopher P. Denton,
  • Yasser El-Sherbiny,
  • Paul J. Meakin,
  • Rebecca L. Ross,
  • Francesco Del Galdo

摘要

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.