Nathan K Archer1, Jay-Hyun Jo2, Steven K Lee1, Dongwon Kim1, Barbara Smith3, Roger V Ortines1, Yu Wang1, Mark C Marchitto1, Advaitaa Ravipati1, Shuting S Cai1, Carly A Dillen1, Haiyun Liu1, Robert J Miller1, Alyssa G Ashbaugh1, Angad S Uppal1, Michiko K Oyoshi4, Nidhi Malhotra4, Sabine Hoff5, Luis A Garza1, Heidi H Kong2, Julia A Segre6, Raif S Geha4, Lloyd S Miller7. 1. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Md. 2. Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md. 3. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Md. 4. Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass. 5. Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass; TRG Oncology III, Drug Discovery, Bayer AG, Berlin, Germany. 6. Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. 7. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Md. Electronic address: lloydmiller@jhmi.edu.
Abstract
BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1β levels, but the mechanisms by which IL-1α, IL-1β, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1β levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1β protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.
BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1β levels, but the mechanisms by which IL-1α, IL-1β, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1β levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1β protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.
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