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

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. We sought to determine the impact of RIPK1 on cell death and inflammation in LP and CLE. 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. 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. Inhibition of RIPK1 targets 2 major pathogenic events in LP and CLE: epidermal cell death and type 1-mediated skin inflammation.