1. IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in systemic sclerosis epidermis.
- Author
-
Russo, Barbara, Borowczyk, Julia, Cacialli, Pietro, Moguelet, Philippe, Truchetet, Marie-Elise, Modarressi, Ali, Brembilla, Nicolò C, Bertrand, Julien, Boehncke, Wolf-Henning, and Chizzolini, Carlo
- Subjects
- *
INTERLEUKINS , *FIBRONECTINS , *BIOPSY , *CELL culture , *SKIN , *CULTURE media (Biology) , *SYSTEMIC scleroderma , *FIBROSIS , *RNA , *GENE expression , *COMPARATIVE studies , *FLUORESCENT antibody technique , *IN situ hybridization , *ENZYME-linked immunosorbent assay , *EXTRACELLULAR space , *KERATINOCYTES - Abstract
Objectives Evidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis. Whether IL-25, an IL-17 family member regulating many epidermal functions, takes part in skin fibrosis is unknown. Here we address the role of IL-25 in skin fibrosis. Methods The expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and seven healthy donor (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EEs was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (Col-I), and fibronectin production by fibroblasts was assessed by ELISA. Results SSc epidermis expressed lower levels of IL-25 compared with HDs. In EEs, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix remodelling. Compared with control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6 and IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. Conclusions These results show that IL-25 participates in skin homeostasis, and its decreased expression in SSc may contribute to skin fibrosis by favouring extracellular matrix deposition over degradation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF