Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release
Open accessAbstract
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-1α and IL-1β levels, but the mechanisms by which IL-1α, IL-1β, 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-1α and IL-1β 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-1α and IL-1β 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-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 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-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 potential therapeutic targets.
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IL-1α has been considered a therapeutic target in atopic dermatitis.
“As one of the first and most important mediators in antigen presentation and induction of the inflammatory cascade, IL-1α has been considered as a therapeutic target in AD69.”
From Atopic dermatitis: an expanding therapeutic pipeline for a complex disease (2022) · cites this paper as [69]
IL-1α is a proinflammatory cytokine released by keratinocytes after injury and by skin dysbiosis.
“IL-1α is a proinflammatory cytokine released by keratinocytes after injury and by skin dysbiosis69.”
From Atopic dermatitis: an expanding therapeutic pipeline for a complex disease (2022) · cites this paper as [69]
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References 66 · Cited by 82
- Authors
- Archer, N. K., Jo, J.-H., Lee, S. K., Kim, D., Smith, B., Ortines, R. V., Wang, Y., Marchitto, M. C., Ravipati, A., Cai, S. S., Dillen, C. A., Liu, H., Miller, R. J., Ashbaugh, A. G., Uppal, A. S., Oyoshi, M. K., Malhotra, N., Hoff, S., Garza, L. A., Kong, H. H., Segre, J. A., Geha, R. S., & Miller, L. S.
- Affiliations
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Boston Children's Hospital (US)
- Corresponding author
- Miller, Lloyd S.
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 143
- Issue
- 4
- Pages
- 1426-1443.e6
- ISSN
- 0091-6749 (ISSN-L)
- PMC
- PMC6424655
- OpenAlex
- W2890876748
- Cited by
- 82
- References
- 66
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 15 · 2023: 8 · 2022: 15 · 2021: 14 · 2020: 12 · 2019: 4
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Arthritis and Musculoskeletal and Skin Diseases (R01AR069502)
- National Institute of Allergy and Infectious Diseases (R21AI126896)
- Atopic Dermatitis Research Network (U19AI117673-01)
- Division of Intramural Research (ZIAHG000180-17, ZIABC011558-04)
- US National Institutes of Health
- Department of Health and Human Services
- Food Allergy Research & Education
- HOPE APFED/ARTrust TM Pilot Grant
- Harvard Catalyst Clinical and Translational Research Center (8UL 1TR000170)
- MedImmune
- Pfizer
- Regeneron Pharmaceuticals
- Moderna Therapeutics
- Boehringer Ingelheim
- NIH (S10 RR024550)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- atopic dermatitis, filaggrin deficiency, keratinocytes, IL-1α, IL-1β, skin damage, skin inflammation, MyD88, topical antibiotics, cohousing
- MeSH terms
- Filaggrin Proteins, Animals, Dermatitis, Atopic, Inflammation, Intermediate Filament Proteins, Mice, Inbred BALB C, Keratinocytes, Mice, Knockout, Mice, Interleukin-1alpha, Dysbiosis
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