Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells.
TLR7
c-Jun
dendritic cells
psoriasis
targeted therapy
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
09 04 2021
09 04 2021
Historique:
revised:
28
01
2021
received:
27
03
2020
accepted:
01
02
2021
pubmed:
17
3
2021
medline:
26
10
2021
entrez:
16
3
2021
Statut:
ppublish
Résumé
Toll-like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP-1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c-Jun/AP-1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c-Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c-Jun in DCs or chemical blockade of JNK/c-Jun signaling ameliorates psoriasis-like skin inflammation by reducing IL-23 production in DCs. Importantly, the control of IL-23 and CCL2 by c-Jun is most pronounced in murine type-2 DCs. CCL2 and IL-23 expression co-localize with c-Jun in type-2/inflammatory DCs in human psoriatic skin and JNK-AP-1 inhibition reduces the expression of these targets in TLR7/8-stimulated human DCs. Therefore, c-Jun/AP-1 is a central driver of TLR7-induced immune responses by DCs and JNK/c-Jun a potential therapeutic target in psoriasis.
Identifiants
pubmed: 33724710
doi: 10.15252/emmm.202012409
pmc: PMC8033525
doi:
Substances chimiques
Interleukin-23
0
Transcription Factor AP-1
0
Imiquimod
P1QW714R7M
Banques de données
GEO
['GSE121212']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12409Subventions
Organisme : Austrian Science Fund FWF
ID : DOC 32
Pays : Austria
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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