Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis

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 mitogen...

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Autores principales:	Hanna Niehues, Gijs Rikken, Ivonne M.J.J. van Vlijmen-Willems, Diana Rodijk-Olthuis, Piet E.J. van Erp, Patrick L.J.M. Zeeuwen, Joost Schalkwijk, Ellen H. van den Bogaard
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Dermatology RL1-803
Acceso en línea:	https://doaj.org/article/9e1b2ec8e7654f0fa08e7729bc1f5649
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spelling	oai:doaj.org-article:9e1b2ec8e7654f0fa08e7729bc1f56492021-12-04T04:36:30ZIdentification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis2667-026710.1016/j.xjidi.2021.100066https://doaj.org/article/9e1b2ec8e7654f0fa08e7729bc1f56492022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2667026721000679https://doaj.org/toc/2667-0267Psoriasis 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.Hanna NiehuesGijs RikkenIvonne M.J.J. van Vlijmen-WillemsDiana Rodijk-OlthuisPiet E.J. van ErpPatrick L.J.M. ZeeuwenJoost SchalkwijkEllen H. van den BogaardElsevierarticleDermatologyRL1-803ENJID Innovations, Vol 2, Iss 1, Pp 100066- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Dermatology RL1-803
spellingShingle	Dermatology RL1-803 Hanna Niehues Gijs Rikken Ivonne M.J.J. van Vlijmen-Willems Diana Rodijk-Olthuis Piet E.J. van Erp Patrick L.J.M. Zeeuwen Joost Schalkwijk Ellen H. van den Bogaard Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis
description	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.
format	article
author	Hanna Niehues Gijs Rikken Ivonne M.J.J. van Vlijmen-Willems Diana Rodijk-Olthuis Piet E.J. van Erp Patrick L.J.M. Zeeuwen Joost Schalkwijk Ellen H. van den Bogaard
author_facet	Hanna Niehues Gijs Rikken Ivonne M.J.J. van Vlijmen-Willems Diana Rodijk-Olthuis Piet E.J. van Erp Patrick L.J.M. Zeeuwen Joost Schalkwijk Ellen H. van den Bogaard
author_sort	Hanna Niehues
title	Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis
title_short	Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis
title_full	Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis
title_fullStr	Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis
title_full_unstemmed	Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis
title_sort	identification of keratinocyte mitogens: implications for hyperproliferation in psoriasis and atopic dermatitis
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/9e1b2ec8e7654f0fa08e7729bc1f5649
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Identification of Keratinocyte Mitogens: Implications for Hyperproliferation in Psoriasis and Atopic Dermatitis

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