Glucocorticoid receptor controls atopic dermatitis inflammation via functional interactions with P63 and autocrine signaling in epidermal keratinocytes.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
28 Jul 2024
28 Jul 2024
Historique:
received:
26
01
2024
accepted:
18
07
2024
revised:
16
07
2024
medline:
29
7
2024
pubmed:
29
7
2024
entrez:
28
7
2024
Statut:
epublish
Résumé
Atopic dermatitis (AD), a prevalent chronic inflammatory disease with multifactorial etiology, features epidermal barrier defects and immune overactivation. Synthetic glucocorticoids (GCs) are widely prescribed for treating AD due to their anti-inflammatory actions; however, mechanisms are incompletely understood. Defective local GC signaling due to decreased production of endogenous ligand and/or GC receptor (GR) levels was reported in prevalent inflammatory skin disorders; whether this is a consequence or contributing factor to AD pathology is unclear. To identify the chromatin-bound cell-type-specific GR protein interactome in keratinocytes, we used rapid immunoprecipitation of endogenous proteins and mass spectrometry identifying 145 interactors that increased upon dexamethasone treatment. GR-interacting proteins were enriched in p53/p63 signaling, including epidermal transcription factors with critical roles in AD pathology. Previous analyses indicating mirrored AD-like phenotypes between P63 overexpression and GR loss in epidermis, and our data show an intricate relationship between these transcription factors in human keratinocytes, identifying TP63 as a direct GR target. Dexamethasone treatment counteracted transcriptional up-regulation of inflammatory markers by IL4/IL13, known to mimic AD, causing opposite shifts in GR and P63 genomic binding. Indeed, IL4/IL13 decreased GR and increased P63 levels in cultured keratinocytes and human epidermal equivalents (HEE), consistent with GR down-regulation and increased P63 expression in AD lesions vs normal skin. Moreover, GR knockdown (GR
Identifiants
pubmed: 39069531
doi: 10.1038/s41419-024-06926-w
pii: 10.1038/s41419-024-06926-w
doi:
Substances chimiques
Receptors, Glucocorticoid
0
TP63 protein, human
0
Dexamethasone
7S5I7G3JQL
Transcription Factors
0
Tumor Suppressor Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
535Subventions
Organisme : Generalitat Valenciana (Regional Government of Valencia)
ID : CIPROM22/42
Organisme : Generalitat Valenciana (Regional Government of Valencia)
ID : CIPROM22/42
Informations de copyright
© 2024. The Author(s).
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