Exp Dermatol. 2022 May 10. doi: 10.1111/exd.14605. Online ahead of print.
ABSTRACT
BACKGROUND: Atopic dermatitis (AD) remains a highly heterogenous disorder with a multifactorial aetiology. Whilst keratinocytes are known to play a fundamental role in AD, their contribution to the overall immune landscape in moderate to severe AD is still poorly understood. In order to design new therapeutics, further investigation is needed into common disease pathways at the molecular level.
METHODS: We used publicly available whole-tissue RNAseq data (4 studies) and single-cell RNAseq keratinocyte data to identify genes/pathways that are involved in keratinocyte responses in AD and after dupilumab treatment. Transcripts present in both keratinocytes (single-cell) and whole-tissue, referred to as the keratinocyte-enriched lesional skin (KELS) genes, were analyzed using functional/pathway analysis.
RESULTS: Following statistical testing 2,049 genes (16.8%) were differentially expressed in KELS. Enrichment analyses predicted increases in not only type-1/-2 immune signaling and chemoattraction, but also in EGF-dominated growth factor signaling. We identified complex crosstalk between keratinocytes and immune cells involving a dominant EGF family signature which converges on keratinocytes with potential immunomodulatory and chemotaxis-promoting consequences. Although keratinocytes express the IL4R, we observed no change in EGF signaling in KELS after three months treatment with Dupilumab indicating that this pathway is not modulated by immunotherapy.
CONCLUSIONS: EGF family signaling is significantly dysregulated in AD lesions but is not associated with keratinocyte proliferation. EGF signaling pathways in AD require further study.
PMID:35538596 | DOI:10.1111/exd.14605
