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

Publication date: Available online 19 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): 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 Oyoshi, Nidhi Malhotra, Sabine Hoff, Luis A. Garza, Heidi H. Kong

Abstract

Background

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.

Objective

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.

Methods

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.

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 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.

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 for potential therapeutic targets.

Graphical abstract

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