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

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

SUBMITTER: Archer NK 

PROVIDER: S-EPMC6424655 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature