Mesenchymal Stem Cells Profile in Adult Atopic Dermatitis and Effect of IL4-IL13 Inflammatory Pathway Inhibition In Vivo: Prospective Case-Control Study

Anna Campanati; Monia Orciani; Andrea Marani; Mariangela Di Vincenzo; Simona Magi; Stamatios Gregoriou; Federico Diotallevi; Emanuela Martina; Giulia Radi; Annamaria Offidani

doi:10.3390/jcm11164759

Mesenchymal Stem Cells Profile in Adult Atopic Dermatitis and Effect of IL4-IL13 Inflammatory Pathway Inhibition In Vivo: Prospective Case-Control Study

J Clin Med. 2022 Aug 15;11(16):4759. doi: 10.3390/jcm11164759.

Affiliations

¹ Dermatological Clinic, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, 60020 Ancona, Italy.
² Histology, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, 60126 Ancona, Italy.
³ Pharmacology, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60126 Ancona, Italy.
⁴ Faculty of Medicine, 1st Department of Dermatology-Venereology at Andreas Sygros Hospital, National and Kapodistrian University in Athens, 16121 Athens, Greece.

Abstract

Atopic dermatitis (AD) is an inflammatory disease that typically begins in childhood and may persist into adulthood, becoming a lifelong condition. The major inflammatory mediators of AD are known to be interleukin IL4 and IL13, so Dupilumab, which is able to inhibit both interleukins by blocking the shared IL4Rα subunit, has become an attractive option for treating AD. Mesenchymal stem cells (MSCs) are involved in the onset and development of AD by secreting specific interleukins. The aim of this study was to isolate MSCs from healthy controls (C-MSCs) and patients with AD before (AD-MSCs T0) and after 16 weeks of treatment with Dupilumab (AD-MSCs T16); to evaluate the expression mainly of IL4 and IL13 and of other inflammatory cytokines in C-MSCs, AD-MSCs at T0 and at T16; and to evaluate the efficacy of Dupilumab on MSCs immunobiology. C- and AD-MSCs (T0, T16) were isolated from skin specimens and characterized; the expression/secretion of IL4 and IL13 was evaluated using immuno-cytochemistry (ICC), indirect immune-fluorescence (IIF) and an ELISA test; secretion of IL2, IL4, IL5, IL6, IL10, IL12, IL13, IL17A, Interferon gamma (IFNγ), Tumor necrosis factor alpha (TNFα), Granulocyte Colony-Stimulating Factor (G-CSF), and Transforming Growth Factor beta1 (TGFβ1) were measured with ELISA. IL13 and IL6 were over-expressed, while IL4 was down-regulated in AD-MSCs at T0 compared to C-MSCs. IL6 and IL13 expression was restored after 16 weeks of Dupilumab treatment, while no significant effects on IL4 expression were noted. Finally, IL2, IL5, IL10, IL12, IL17A, INFγ, TNFα, G-CSF, and TGFβ1 were similarly secreted by C- and AD-MSCs. Although Dupilumab blocks the IL4Rα subunit shared by IL4 and IL13, it is evident that its real target is IL13, and its ability to target IL13 in MSCs reinforces the evidence, already known in differentiated cells, of the central role IL13 rather than IL4 in the development of AD. The inflammatory cascade in AD begins at the mesenchymal level, so an upstream therapeutic intervention, able to modify the immunobiology of atopic MSCs, could potentially change the natural history of the disease.

Keywords: atopic dermatitis; biologics; dupilumab; mesenchymal stem cells; psoriasis; regenerative medicine; therapy.

Grants and funding

This research received no external funding.