Kurzen Nils, Mubarak Menna, Eigemann Jessica, Seiringer Peter, Wasserer Sophia, Hillig Christina, Menden Michael, Biedermann Tilo, Schmidt-Weber Carsten B, Eyerich Kilian, Jargosch Manja, Eyerich Stefanie, Lauffer Felix
Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany.
Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany; Department of Dermatology and Venereology, Medical Center, University of Freiburg, Freiburg, Germany.
J Invest Dermatol. 2025 Aug;145(8):1921-1929.e13. doi: 10.1016/j.jid.2024.11.017. Epub 2024 Dec 31.
Lichen planus (LP) is a chronic inflammatory disease affecting the skin, mucosa, nail, and hair. Previous studies demonstrated a pivotal role of type 1 immunity in LP because infiltrating T cells trigger apoptosis and necroptosis in the epidermis. In this study, we investigated the role of DAPK1 in LP with special focus on its role in mediating cell death and inflammation. Bulk RNA sequencing of skin biopsies revealed a high expression of DAPK1 in LP compared with that in psoriasis and atopic dermatitis. DAPK1 expression in human keratinocytes was induced by IFN-γ, TNF, and IL-32. CRISPR/Cas9-mediated DAPK1 knockout led to a decreased rate of cell death and induction of proapoptotic proteins (BAX, cPARP) in human keratinocytes upon stimulation with the supernatant T cells derived from LP skin biopsies. Meanwhile, DAPK1 knockout resulted in an induction of kinases involved in necroptosis (RIPK3) and an upregulation of inflammatory genes (CXCL9, CXCL10, CXCL11, IL32, CCL2) after stimulation with LP supernatant T cells. In summary, we demonstrate that DAPK1 mediates keratinocyte apoptosis under type 1 inflammatory conditions and thereby counteracts necroptosis and regulation of inflammatory genes. These findings point toward previously unreported therapeutic approaches for activating or stabilizing DAPK1 in LP.
