Journal
CELLS
Volume 11, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/cells11030530
Keywords
fibrosis; Scleroderma; Ion channels; CLIC4; morphogens
Categories
Funding
- Susan Cheney Scleroderma fellowship
- Sapienza University of Rome
- Fondazione AIRC (Associazione Italiana Ricerca sul Cancro) [25833]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/S01716X/1]
- National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC)
- NIHR or the Department of Health and Social Care
- BBSRC [BB/S01716X/1] Funding Source: UKRI
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This study reveals that CLIC4 expression is regulated by the signaling crosstalk between TGF-beta, Wnt-3a, and Hh, and that it strongly correlates with the expression of the pro-fibrotic marker alpha-smooth muscle actin. Further investigations demonstrate that inhibiting CLIC4 can reverse morphogen-dependent fibroblast activation.
Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-beta signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a and Hedgehog (Hh) signalling in fibrosis, we investigated their role in CLIC4 upregulation. Here, we show that TGF-beta/SMAD3 co-operates with Wnt3a/beta-catenin and Smoothened/GLI signalling to drive CLIC4 expression in normal dermal fibroblasts, and that the inhibition of beta-catenin and GLI expression or activity abolishes TGF-beta/SMAD3-dependent CLIC4 induction. We further show that the expression of the pro-fibrotic marker alpha-smooth muscle actin strongly correlates with CLIC4 expression in dermal fibroblasts. Further investigations revealed that the inhibition of CLIC4 reverses morphogen-dependent fibroblast activation. Our data highlights that CLIC4 is a common downstream target of TGF-beta, Hh, and Wnt-3a through signalling crosstalk and we propose a potential therapeutic avenue using CLIC4 inhibitors
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