IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in systemic sclerosis epidermis

Rheumatology (Oxford). 2022 Nov 2;61(11):4558-4569. doi: 10.1093/rheumatology/keac044.


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.

Keywords: IL-17E; IL-25; epidermis; extra cellular matrix; fibroblast; fibrosis; keratinocytes; scleroderma; skin; systemic sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Epidermis / metabolism
  • Epidermis / pathology
  • Fibroblasts / metabolism
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Interleukin-17* / metabolism
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Keratinocytes* / metabolism
  • Matrix Metalloproteinase 1 / metabolism
  • Scleroderma, Systemic* / pathology
  • Skin / pathology


  • Culture Media, Conditioned
  • Fibronectins
  • Interleukin-17
  • Interleukin-6
  • Interleukin-8
  • Matrix Metalloproteinase 1
  • IL25 protein, human