Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions
Open accessAbstract
Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.
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AHR itself is beneficial for the skin barrier, as AHR-deficient mice show skin inflammation, epidermal barrier dysfunction, and skin dysbiosis.
“In contrast to the toxic effects of persistently activated AHR, AHR itself is beneficial for the skin barrier, as the AHR-deficient mice show skin inflammation, epidermal barrier dysfunction, and skin dysbiosis (57, 58).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [58]
The Results section (‘AhR Deficiency in Nonhematopoietic Cells Causes Exacerbated Skin Inflammation’; page not provided) reports exacerbated skin inflammation, epidermal pathology, and reduced keratinocyte differentiation in AhR-deficient mice. It does not establish epidermal barrier dysfunction or skin dysbiosis; those parts of the claim are unsupported by our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredAHR is essential in maintaining normal skin barrier function and cutaneous homeostasis.
“AHR is essential in maintaining normal skin barrier function and cutaneous homeostasis (57, 58).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [58]
The Discussion says AhR signaling promotes skin barrier formation and helps control skin homeostasis during inflammatory responses. The Results show that AhR-deficient skin cells have exaggerated inflammatory responses. These passages support a role for AhR, but do not establish that it is essential for maintaining normal barrier function and homeostasis in the absence of inflammation; page numbers were not available in our copy. (LLM, conf=0.85)
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References 51 · Cited by 373
- Authors
- Di Meglio, P., Duarte, J. H., Ahlfors, H., Owens, N. D. L., Li, Y., Villanova, F., Tosi, I., Hirota, K., Nestle, F. O., Mrowietz, U., Gilchrist, M. J., & Stockinger, B.
- Affiliations
- National Institute for Medical Research (GB)
- King's College London (GB)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Stockinger, Brigitta
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 40
- Issue
- 6
- Pages
- 989-1001
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4067745
- OpenAlex
- W2040177546
- Cited by
- 373
- References
- 51
- Citations by year
- 2026: 27 · 2025: 27 · 2024: 39 · 2023: 30 · 2022: 31 · 2021: 34 · 2020: 26 · 2019: 32 · 2018: 31 · 2017: 28 · 2016: 32 · 2015: 23 · 2014: 12
- FWCI
- 14.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (100910)
- National Institute for Health and Care Research
- King's College London
- Medical Research Council
- Leibniz-Gemeinschaft
- FP7 Ideas: European Research Council (232782)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Rheumatology › Spondyloarthritis Studies and Treatments
- Keywords
- aryl hydrocarbon receptor, psoriasis, skin inflammation, FICZ, imiquimod-induced skin inflammation, keratinocytes, AP-1 transcription factor, AhR agonists, AhR antagonists, environmental stimuli, autoimmune disease
- MeSH terms
- Imiquimod, Adjuvants, Immunologic, Aminoquinolines, Animals, Aryl Hydrocarbon Hydroxylases, Azo Compounds, Carbazoles, Environmental Exposure, Humans, Inflammation, Psoriasis, Pyrazoles, Skin, Transcription Factors, Signal Transduction, Keratinocytes, Up-Regulation, Cytokines, Receptors, Aryl Hydrocarbon, Mice, Knockout, Cytochrome P-450 CYP1A1, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Cytochrome P-450 CYP1B1
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