Deficiency of vitamin D receptor in keratinocytes augments dermal fibrosis and inflammation in a mouse model of HOCl-induced scleroderma

Scleroderma, characterized by extensive fibrosis and vascular alterations, involves excessive fibroblast activation, uncontrolled inflammation, and abnormal collagen deposition. Previous studies showed that administrations of either 1,25(OH)(2)D-3 or vitamin D analog effectively decreased or reversed skin fibrosis by regulating the extracellular matrix homeostasis. The actions of 1,25(OH)(2)D-3 are mediated by the vitamin D receptor (VDR), a transcription regulator crucial for skin homeostasis. Although evidence suggests that keratinocyte-fibroblast interaction influences the development of scleroderma, the role of keratinocytes in scleroderma remains unknown. Here, we demonstrated that the ablation of VDR in keratinocytes greatly exacerbated dermal fibrosis in HOCl-induced scleroderma in mice. The deficiency of VDR in the epidermis marked increased dermal thickness, inflammatory cell infiltration, and severe collagen deposition in comparison to the control group in HOCl-treated skin. Moreover, significant elevations in expression levels of mRNA for collagen overproduction (Col1A1, Col1A2, Col3A1, alpha-SMA, MMP9, TGF-beta 1) and proinflammatory cytokines (IL-1 beta, IL-6, CXCL1, CXCL2) were observed in VDR conditional KO versus control mice following HOCI treatment. Collectively, these results suggest that VDR in keratinocytes plays a pivotal role in scleroderma progression, and the interplay between keratinocytes and fibroblasts deserves more attention regarding the exploration of the pathogenesis and treatment for scleroderma. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study demonstrates that the ablation of VDR in keratinocytes greatly exacerbates dermal fibrosis in HOCl-induced scleroderma in mice, suggesting that the interplay between keratinocytes and fibroblasts plays a crucial role in the pathogenesis and treatment of scleroderma.