Arthritis research & therapy · 2025
Transforming growth factor beta (TGF-β) induces type 1 interferon signalling in systemic sclerosis keratinocytes through the chloride intracellular channel 4 (CLIC4).
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Wasson Christopher W, Dibb Sophie L, Caballero-Ruiz Begoña, Bamigbola Ifeoluwa E, Di Donato Stefano, Madourie-Clavane Eva M, Wells Rebecca, Kakkar Vishal, De Lorenzis Enrico, Bryon Jessica, Derrett-Smith Emma, Denton Christopher P, El-Sherbiny Yasser, Meakin Paul J, Ross Rebecca L, Del Galdo Francesco
Аннотация
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.
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.