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

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.

Anti‐Inflammatory Effect of Dental Pulpa Mesenchymal Stem Cell Exosomes Loaded Mucoadhesive Hydrogel on Mice with Dental Nickel Hypersensitivity

“…[32] The fact that DPMSCs exosomes change the Th2 responses in the inflammatory tissue area in dental nickel hypersensitivity toward Th1 is compatible with studies in the literature. [32,33] In this study, IL-4-secreting CD4+ T lymphocyte ratios significantly decreased for dental nickel hypersensitivity in the experimental group exosome applied together with the hydrogel (Group 4) and in the group treated with exosome alone (Group 6) after the seventh day (in the results of the 14th day) compared to (Group 3). The results obtained in the immunological analyzes are supported by the results obtained in the immunohistochemical studies.…”

miRNAs, Mesenchymal Stromal Cells and Major Neoplastic and Inflammatory Skin Diseases: A Page Being Written: A Systematic Review

“…MSCs are multipotent cells residing in multiple tissues with the capacity for selfrenewal and differentiation into various cell types [9,10]. Our previous works confirmed that different pathologies, ranging from the dermatologic to the fibrotic ones [11][12][13][14][15][16][17][18][19][20], arise at the staminal level: MSCs show the same dysregulated pathological properties found in differentiated cells, opening up the hypothesis that the onset of the diseases could be backdated at the stem level.…”

A Systematic Review of Atopic Dermatitis: The Intriguing Journey Starting from Physiopathology to Treatment, from Laboratory Bench to Bedside

“…Starting from these considerations, today, dealing with AD is more than “treating chronic eczema”. The therapeutic strategies available and those that will appear soon have the ambition to modify not only the clinical course but also the natural history of the disease, preventing the cumulative burden that the disease has on the lives of affected patients [ 71 , 72 ]. Understanding AD pathogenesis in depth may represent a starting point that is useful for understanding how the therapeutic panorama of AD is being enriched, through a “bench to bedside” journey [ 72 ].…”