incb039110 and Lichen-Planus

Cutaneous lupus erythematosus (CLE) is an interferon (IFN) -driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model.. Lesional skin of patients with different CLE subtypes and healthy controls (. Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE. IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1

Topics: Animals; Azetidines; Cell Line; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Induction; Enzyme Inhibitors; Exodeoxyribonucleases; Gene Expression Regulation; Humans; Isonicotinic Acids; Janus Kinase 1; Keratinocytes; Lichen Planus; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid; Mice; Mice, Inbred C57BL; Models, Immunological; Phosphoproteins; Specific Pathogen-Free Organisms