Inhibition of RIPK1 prevents keratinocyte cell death and reduces skin inflammation in type 1–mediated chronic inflammatory skin diseases

BACKGROUND: Type 1-mediated chronic inflammatory skin diseases affect skin, hair, nails, and mucosa and dramatically impact patients' quality of life. The 2 most prominent examples are lichen planus (LP) and cutaneous lupus erythematosus (CLE). Various cell death pathways are activated in both diseases, including apoptosis and necroptosis. RIPK1 is a key regulator of programmed cell death and thus represents a potential new target for treatment of these diseases. OBJECTIVE: We sought to determine the impact of RIPK1 on cell death and inflammation in LP and CLE. METHODS: RNA sequencing of inflammatory skin diseases (n = 179) assessed cell death, hypothermia, and inflammatory markers affected by eclitasertib, a novel RIPK1 inhibitor, in human cells, murine TNF-α-induced systemic inflammatory response syndrome model, reconstructed human epidermis, and ex vivo skin biopsy culture. RESULTS: Markers of apoptosis (CASPASE8) and necroptosis (RIPK3, MLKL) are upregulated in LP and CLE. Eclitasertib restored body temperature when orally administered 15 minutes after TNF-α injection in the murine systemic inflammatory response syndrome model. RIPK1 inhibition prevented keratinocyte cell death; normalized epidermal architecture; and decreased release of IL-1α, IL-1β, TNF-α, and CCL20 in reconstructed human epidermis on stimulation with LP and CLE T-cell supernatant. Ex vivo culture of LP and CLE biopsy specimens with eclitasertib reduced expression of disease-specific genes and downregulated pathways associated with inflammation. CONCLUSIONS: Inhibition of RIPK1 targets 2 major pathogenic events in LP and CLE: epidermal cell death and type 1-mediated skin inflammation.