Inflammatory Mediators Suppress FGFR2 Expression in Human Keratinocytes to Promote Inflammation

Fibroblast growth factors (FGFs) are key orchestrators of development, tissue homeostasis and repair. FGF receptor (FGFR) deficiency in mouse keratinocytes causes an inflammatory skin phenotype with similarities to atopic dermatitis, but the human relevance is unclear. Therefore, we generated human...

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Bibliographic Details
Published in:Molecular and cellular biology 2024-11, Vol.44 (11), p.489-504
Main Authors: Ferrarese, Luca, Koch, Michael, Baumann, Artemis, Bento-Lopes, Liliana, Wüst, Daria, Berest, Ivan, Kopf, Manfred, Werner, Sabine
Format: Article
Language:English
Subjects:
Animals
atopic dermatitis
bioinformatics
Cell Biology
Cells, Cultured
CRISPR-Cas Systems
cytokines
Cytokines - metabolism
Dermatitis, Atopic - genetics
Dermatitis, Atopic - metabolism
Dermatitis, Atopic - pathology
Down-Regulation
fibroblast growth factor receptor 2
fibroblasts
homeostasis
Humans
inflammation
Inflammation - genetics
Inflammation - metabolism
Inflammation Mediators - metabolism
keratinocytes
Keratinocytes - metabolism
Mice
pathogenesis
phenotype
Receptor, Fibroblast Growth Factor, Type 2 - genetics
Receptor, Fibroblast Growth Factor, Type 2 - metabolism
sequence analysis
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Summary:Fibroblast growth factors (FGFs) are key orchestrators of development, tissue homeostasis and repair. FGF receptor (FGFR) deficiency in mouse keratinocytes causes an inflammatory skin phenotype with similarities to atopic dermatitis, but the human relevance is unclear. Therefore, we generated human keratinocytes with a CRISPR/Cas9-induced knockout of . Loss of this receptor promoted the expression of interferon-stimulated genes and pro-inflammatory cytokines under homeostatic conditions and in particular in response to different inflammatory mediators. Expression of FGFR2 itself was strongly downregulated in cultured human keratinocytes exposed to various pro-inflammatory stimuli. This is relevant , because bioinformatics analysis of bulk and single-cell RNA-seq data showed strongly reduced expression of in lesional skin of atopic dermatitis patients, which likely aggravates the inflammatory phenotype. These results reveal a key function of FGFR2 in human keratinocytes in the suppression of inflammation and suggest a role of FGFR2 downregulation in the pathogenesis of atopic dermatitis and possibly other inflammatory diseases.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1080/10985549.2024.2399766