Deficiency of Med1 in keratinocytes augments dermal fibrosis and inflammation in scleroderma.

Abstract

Scleroderma is primarily characterized by widespread fibrosis and vascular dysfunction, with the abnormal activation of fibroblasts (FBs) being the most critical pathological features. While FB's activation has traditionally been attributed to infiltrating immune cells such as macrophages and T cells, emerging evidence highlights that keratinocytes (KCs) in scleroderma exhibit significant functional impairment. KCs secrete multiple key inflammatory factors that contribute to disease progression. Previous studies have identified the coactivator Mediator subunit 1 (Med1) as essential for regulating KCs proliferation, differentiation, and epidermal barrier homeostasis, in addition to modulating inflammatory factor expression. Thus, this study aims to investigate whether Med1 in KCs contributes to scleroderma pathogenesis. We established a bleomycin (BLM)-induced scleroderma model using Med1mice and K14Cre-Med1mice to investigate the impact of Med1 in KCs. Our results showed that Med1 deficiency in KCs exacerbated dermal collagen deposition and skin inflammation. Although Med1 serves as a crucial coactivator for the transcription of numerous genes, we found that its deficiency in KCs significantly promoted the activation of the PPARγ signaling pathway and upregulated the expression of multiple pro-inflammatory factors (e.g., OSM, IL-1β, CXCL2). Mechanistically, this probably occurred via the regulation of the repressor SMRT. Further, stimulation of FBs with OSM and IL-1β revealed that these KC-derived cytokines potently induced the expression of genes associated with inflammation and collagen synthesis. In conclusion, this study establishes a critical role for Med1 in KCs during scleroderma progression and highlights its potential as a therapeutic target for modulating inflammatory and fibrotic responses in scleroderma.