Dissecting the role of inflammation in the pathogenesis of ichthyosis with confetti

Summary: Abstract Body: Ichthyosis with confetti (IWC) is an autosomal-dominant genetic skin condition caused by damaging variants in keratin 1 or 10. Patients with IWC have severely red, scaly skin and develop “confetti spots” of genetically reverted, histologically normal-appearing skin. We aimed to determine whether IWC shares the Th17 immunologic signature shown in other monogenic forms of ichthyosis and whether targeted immune-based therapies could ameliorate inflammation in IWC. Using RNA in situ hybridization, we demonstrated that IWC skin lacked IL-17A+ T cells but had increased levels of IL-36G in the suprabasal epidermis. IL36G elevation was specific to affected skin and at levels similar to psoriasis and atopic dermatitis. We used an inducible transgenic mouse model to express IWC-mutant Krt10 in mice and profiled skin at multiple time points using single cell RNA sequencing. Compared to wildtype controls, suprabasal keratinocytes from IWC mice expressed high levels of epithelial damage markers, antimicrobial calprotectin genes, and IL-36g. Ligand-receptor analysis predicted endogenous products from mutant keratinocytes to activate toll-like receptors on myeloid cells, fibroblasts, and other keratinocytes. Given the demonstrated role of IL-36 ligands in driving psoriasiform dermatitis in mouse models, we crossed IWC mice to IL36 receptor knockout mice. In Krt10-mutant, IL36R knockout-mice, skin pathology (scaling, erythema) remained unchanged and transcripts related to epidermal damage and innate immunity were increased at similar levels to IWC mice. The cellular interactions revealed by our dataset inform our understanding of patterns of inflammation driven by skin barrier dysfunction. Our results indicate that although IL-36 ligands are increased in our mouse model of IWC, inhibiting this inflammatory signal does not ameliorate the skin phenotype. Ryland D. Mortlock^{2, 1, 3}, Diana A. Yanez^{2, 3, 4}, Jing Zhou², Alicia Little², William Damsky^{2, 4}, Keith Choate^{2, 1, 4} 1. Genetics, Yale University School of Medicine, New Haven, CT, United States. 2. Dermatology, Yale University School of Medicine, New Haven, CT, United States. 3. Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, United States. 4. Pathology, Yale University School of Medicine, New Haven, CT, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics