Dysfunctional Keratinocytes Increase Dermal Inflammation in Systemic Sclerosis: Results From Studies Using...

Area of Science:

• Dermatology and immunology
• Cell biology
• Molecular biology

Background:

• Keratinocyte-fibroblast interactions are dysregulated in systemic sclerosis (SSc).
• Epidermal dysfunction may contribute to dermal homeostasis abnormalities in SSc.

Purpose of the Study:

• To investigate epidermal dysfunction in SSc.
• To determine the effects of SSc epidermal dysfunction on dermal homeostasis.

Main Methods:

• Generated epidermal equivalents (EEs) from healthy donors and SSc patients.
• Evaluated EE markers of proliferation, differentiation, and activation via immunohistochemistry.
• Performed RNA sequencing on EEs and stimulated fibroblasts with EE conditioned medium (CM).

Main Results:

• SSc EEs displayed aberrant differentiation, increased activation markers, and reduced mitosis compared to healthy EEs.
• RNA sequencing revealed lower homeobox gene expression and enhanced metabolic/oxidative stress pathways in SSc EEs.
• SSc EE CM significantly increased fibroblast production of IL-6, IL-8, MMP-1, collagen I, and fibronectin, more so than healthy EE CM.

Conclusions:

• SSc EEs replicate in vivo SSc epidermis characteristics, indicating intrinsic keratinocyte differentiation defects possibly linked to homeobox gene dysregulation.
• Increased metabolic and oxidative stress in SSc epidermis may promote chronic dermal inflammation and fibrosis.