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Updated: May 20, 2025

Generation and Culturing of Primary Human Keratinocytes from Adult Skin
Published on: December 22, 2017
Orchestration of Skin Pathology in Cutaneous Lupus Erythematosus by HLA Class I Down-Regulated Senescent Epidermal
Sena Yamamoto1, Yuki Saito2, Tsukasa Sato1
1Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan.
Objective:
This study investigates the role of senescent epidermal basal cells in cutaneous lupus erythematosus (CLE) pathogenesis using skin samples from patients with CLE and a mouse model of systemic lupus erythematosus (SLE).
Methods:
Cellular senescence profiling used datasets from the NCBI GEO database and Accelerating Medicines Partnership (AMP) Phase 1-Metro. Gene array data from GSE184989 (CLE, n = 68; control, n = 4), single-cell RNA sequencing data from GSE186476 (CLE, n = 7; control, n = 14), and AMP Phase 1-Metro (SLE, n = 17) were used. In vitro experiments further examined the expression of p21WAF1/CIP1, Type I interferon (IFN), HLA class I (HLA-I), and epidermal growth factor receptor (EGFR) signaling. Pharmacological clearance of senescent cells was performed using the senolytic drug fisetin in the SLE mouse model.
Results:
p21WAF1/CIP1-high senescent epidermal basal cells in patients with CLE exhibit high Type I IFN expression. These cells enhance IFN signaling in surrounding normal epidermal basal cells, leading to increased HLA-I expression. In contrast, senescent epidermal cells up-regulate epidermal growth factor receptor signaling, which downregulates HLA-I expression, allowing them to evade immune surveillance. This heterogeneity of HLA-I expression promotes CD8-positive T-mediated toxicity against normal epidermal basal cells, resulting in their apoptosis. Pharmacological clearance of senescent epidermal basal cells improved SLE-like skin lesions.
Conclusion:
Senescent cells create a microenvironment that directs cytotoxic T cell-mediated responses against normal epidermis in patients with CLE, contributing to disease pathology. Targeting senescent cells and their signaling pathways may offer novel therapeutic strategies for patients with skin lesions from CLE and SLE.
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