Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis.
3D, three-dimensional
AD, atopic dermatitis
ERK, extracellular signal‒regulated kinase
EdU, 5-ethynyl-2′-deoxyuridine
HEE, human epidermal equivalent
KC, keratinocyte
KGF, keratinocyte GF
MEK, MAPK/ extracellular signal‒regulated kinase kinase
STAT, signal transducer and activator of transcription
Th, T helper
Journal
JID innovations : skin science from molecules to population health
ISSN: 2667-0267
Titre abrégé: JID Innov
Pays: Netherlands
ID NLM: 101776173
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
received:
12
03
2021
revised:
12
07
2021
accepted:
09
08
2021
entrez:
11
2
2022
pubmed:
12
2
2022
medline:
12
2
2022
Statut:
epublish
Résumé
Psoriasis and atopic dermatitis are chronic inflammatory skin diseases characterized by keratinocyte (KC) hyperproliferation and epidermal acanthosis (hyperplasia). The milieu of disease-associated cytokines and soluble factors is considered a mitogenic factor; however, pinpointing the exact mitogens in this complex microenvironment is challenging. We employed organotypic human epidermal equivalents, faithfully mimicking native epidermal proliferation and stratification, to evaluate the proliferative effects of a broad panel of (literature-based) potential mitogens. The KC GF molecule, the T-helper 2 cytokines IL-4 and IL-13, and the psoriasis-associated cytokine IL-17A caused acanthosis by hyperplasia through a doubling in the number of proliferating KCs. In contrast, IFN-γ lowered proliferation, whereas IL-6, IL-20, IL-22, and oncostatin M induced acanthosis not by hyperproliferation but by hypertrophy. The T-helper 2‒cytokine‒mediated hyperproliferation was Jak/signal transducer and activator of transcription 3 dependent, whereas IL-17A and KC GF induced MAPK/extracellular signal‒regulated kinase kinase/extracellular signal‒regulated kinase‒dependent proliferation. This discovery that key regulators in atopic dermatitis and psoriasis are direct KC mitogens not only adds evidence to their crucial role in the pathophysiological processes but also highlights an additional therapeutic pillar for the mode of action of targeting biologicals (e.g., dupilumab) or small-molecule drugs (e.g., tofacitinib) by the normalization of KC turnover within the epidermal compartment.
Identifiants
pubmed: 35146480
doi: 10.1016/j.xjidi.2021.100066
pii: S2667-0267(21)00067-9
pmc: PMC8801538
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100066Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021 The Authors.
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