| First Author | Archer NK | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 143 |
| Issue | 4 | Pages | 1426-1443.e6 |
| PubMed ID | 30240702 | Mgi Jnum | J:295264 |
| Mgi Id | MGI:6453721 | Doi | 10.1016/j.jaci.2018.08.042 |
| Citation | Archer NK, et al. (2019) Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1alpha release. J Allergy Clin Immunol 143(4):1426-1443.e6 |
| abstractText | 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-1alpha and IL-1beta levels, but the mechanisms by which IL-1alpha, IL-1beta, 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-1alpha and IL-1beta 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-1alpha and IL-1beta 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-1alpha release from keratinocytes. IL-1alpha 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-1alpha localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1alpha release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets. |
