Title |
Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release
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Published in |
The Journal of Allergy and Clinical Immunology, September 2018
|
DOI | 10.1016/j.jaci.2018.08.042 |
Pubmed ID | |
Authors |
Nathan K Archer, Jay-Hyun Jo, Steven K Lee, Dongwon Kim, Barbara Smith, Roger V Ortines, Yu Wang, Mark C Marchitto, Advaitaa Ravipati, Shuting S Cai, Carly A Dillen, Haiyun Liu, Robert J Miller, Alyssa G Ashbaugh, Angad S Uppal, Michiko K Oyoshi, Nidhi Malhotra, Sabine Hoff, Luis A Garza, Heidi H Kong, Julia A Segre, Raif S Geha, Lloyd S Miller |
Abstract |
Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis and skin injury from scratching. In particular, the barrier defective epidermis of AD patients with loss-of-function filaggrin mutations has increased IL-1α and IL-1β levels but the mechanisms by which IL-1α and/or IL-1β are induced and whether they contribute to the aberrant skin inflammation in AD is unknown. We sought to determine the mechanisms by which skin injury, dysbiosis and increased epidermal IL-1α and IL-1β contribute to the development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice. Skin injury of wild-type, filaggrin-deficient (ft/ft), and MyD88-deficient ft/ft mice was performed and ensuing skin inflammation was evaluated by digital photography, histologic analysis and flow cytometry. IL-1α and IL-1β protein expression was measured by ELISA and visualized by immunofluorescence and immuno-electron microscopy. The composition of skin microbiome was determined by 16S rDNA sequencing. 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 co-housing 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. 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 for potential therapeutic targets. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 84 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 13 | 15% |
Student > Ph. D. Student | 10 | 12% |
Student > Master | 8 | 10% |
Other | 6 | 7% |
Professor | 4 | 5% |
Other | 16 | 19% |
Unknown | 27 | 32% |
Readers by discipline | Count | As % |
---|---|---|
Immunology and Microbiology | 13 | 15% |
Medicine and Dentistry | 11 | 13% |
Biochemistry, Genetics and Molecular Biology | 10 | 12% |
Nursing and Health Professions | 4 | 5% |
Agricultural and Biological Sciences | 4 | 5% |
Other | 14 | 17% |
Unknown | 28 | 33% |