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

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

doi:10.1016/j.xjidi.2021.100066

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

JID Innov. 2021 Oct 22;2(1):100066. doi: 10.1016/j.xjidi.2021.100066. eCollection 2022 Jan.

Authors

Hanna Niehues¹, Gijs Rikken¹, Ivonne M J J van Vlijmen-Willems¹, Diana Rodijk-Olthuis¹, Piet E J van Erp¹, Patrick L J M Zeeuwen¹, Joost Schalkwijk¹, Ellen H van den Bogaard¹

Affiliation

¹ Department of Dermatology, Radboud University Medical Center (Radboudumc), Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands.

Abstract

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.

Keywords: 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.