Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release

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-1 alpha and IL-1 beta levels, but the mechanisms by which IL-1 alpha, IL-1 beta, 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-1 alpha and IL-1 beta 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-1 alpha and IL-1 beta 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-1 alpha release from keratinocytes. IL-1 alpha 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-1 alpha localization. Conclusions: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1 alpha release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.