Evaluation of expression of Toll-Like Receptors 7 and 9, proliferation, and cytoskeletal biomarkers in plaque and guttate psoriasis: A pilot morphological study

Prignano, Francesca; Lombardo, Giulia; Indino, Serena; Ricceri, Federica; Cornaghi, Laura; Donetti, Elena

doi:10.4081/ejh.2021.3218

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…The absence of a persistent modulation of TLR2/TLR4 expression after exposure either to IL-22 or to IL-23 in our experimental conditions can thus be meaningful. In parallel, the limited effect exerted by IL-22 and IL-23 on TLR7/TLR9 expression should be discussed based on recent observations reporting their upregulation in plaque psoriasis biopsies [61] and after the incubation of 3D organotypic cultures of normal human skin with TNF-alpha, IL-17, IL-22, IL-23, which can reproduce the psoriatic plaque milieu [42]. Both evidences suggest that a complete psoriatic microenvironment is required to modulate TLR7 and TLR9 expression and that a single cytokine is not able to induce any significant tuning in the considered experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Th2 Cytokines Affect the Innate Immune Barrier without Impairing the Physical Barrier in a 3D Model of Normal Human Skin

Donetti

Riva

Indino

et al. 2023

JCM

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(1) Background: Atopic dermatitis is one of the most common inflammatory skin diseases characterized by T helper (Th) 2 and Th22 cells producing interleukin (IL)-4/IL-13 and IL-22, respectively. The specific contribution of each cytokine to the impairment of the physical and the immune barrier via Toll-like receptors (TLRs) is poorly addressed concerning the epidermal compartment of the skin. (2) Methods: The effect of IL-4, IL-13, IL-22, and the master cytokine IL-23 is evaluated in a 3D model of normal human skin biopsies (n = 7) at the air–liquid interface for 24 and 48 h. We investigated by immunofluorescence the expressions of (i) claudin-1, zonula occludens (ZO)-1 filaggrin, involucrin for the physical barrier and (ii) TLR2, 4, 7, 9, human beta-defensin 2 (hBD-2) for the immune barrier. (3) Results: Th2 cytokines induce spongiosis and fail in impairing tight junction composition, while IL-22 reduces and IL-23 induces claudin-1 expression. IL-4 and IL-13 affect the TLR-mediated barrier largely than IL-22 and IL-23. IL-4 early inhibits hBD-2 expression, while IL-22 and IL-23 induce its distribution. (4) Conclusions: This experimental approach looks to the pathogenesis of AD through molecular epidermal proteins rather than cytokines only and paves the way for tailored patient therapy.

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Section: Discussionmentioning

confidence: 99%

Th2 Cytokines Affect the Innate Immune Barrier without Impairing the Physical Barrier in a 3D Model of Normal Human Skin

Donetti

Riva

Indino

et al. 2023

JCM

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“…Among keratins, K16 and K17 are key early barrier alarmins and, if upregulated, can alter proliferation, cell adhesion, and migration [Zhang et al, 2019]. K17 is not expressed in any epidermal layer in normal human skin, but it is known to be an important marker of epithelial cell proliferation [Nichols and Katiyar, 2010], in particular in psoriatic plaques, where the chronic pro-inflammatory milieu promotes cell proliferation [Zhang et al, 2019;Prignano et al, 2021]. In 3D organotypic cultures of normal human skin, K17 expression was specifically induced by the pro-inflammatory psoriatic cytokine IL-17, which inhibits, in parallel, cell proliferation [Donetti et al, 2020].…”

Section: Introductionmentioning

confidence: 99%

Keratin 17 as a Marker of UVB-Induced Stress in Human Epidermis and Modulation by Vitis vinifera Extract

Lombardo

Melzi²,

Indino

et al. 2021

Cells Tissues Organs

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Human epidermis responds to ultraviolet (UV)B-induced damage by tolerating it, restoring it, or undergoing programmed cell death when the damage is massive. Recently, compounds rich in polyphenols, such as Vitis vinifera L. leaf extract (VVLe), have attracted a lot of interest for skin protection. We investigated the effect of VVLe pre-treatment (1 h) in a 2D model of HaCaT cells and in 3D organotypic cultures of normal human skin exposed to a single UVB dose to study the immediate specific events 1 h and the response orchestrated in the epidermal layer 24 h after irradiation, respectively. In both models, transmission electron microscopy analysis was carried out. The expression of the inducible keratin K17, the activation of both pSTAT3 and Nuclear Factor (NF)-κB signalling pathways, and the epidermal distribution of Toll-Like Receptor (TLR) 4 were assessed by immunofluorescence in the 2D and 3D model. In 3D organotypic cultures, thanks to the preservation of a multi-layered structure, the epidermal distribution of the differentiation biomarkers K10 and K14 as well as of K16 was analysed by immunofluorescence, while the release of interleukin (IL)-8 was evaluated by ELISA. In skin bioptic fragments, cytotoxicity and genotoxicity were investigated by LDH assay and Alkaline Comet assay, respectively, and then compared to cell proliferation. The epidermal distribution of the histone γ-H2AX, indicating the fragmented DNA, was analysed by immunofluorescence. In both experimental models, VVLe tuned UVB-induced K17 expression to a different extent in HaCaT cells and in the skin. In HaCaT cells, pSTAT3 activation was induced by UVB and reverted by VVLe pre-treatment. TLR4 expression was triggered by UVB in both models, but VVLe pre-treatment abolished this event only in HaCaT cells. NF-κB immunostaining increased both in the nucleus and in the cytoplasm only in HaCaT cells after UVB irradiation. In all irradiated skin samples, VVLe pre-treatment was not able to revert the inhibition of epidermal proliferation, K16 expression, and IL-8 secretion. The effectiveness of VVLe in contrasting the irradiation-induced genotoxicity still remains unclear. In conclusion, our study clearly shows that K17 is a robust marker induced in keratinocytes upon UVB stimulation and that this event can be reverted by a pre-treatment with VVLe. On the whole, these observations represent a novelty in the scenario of the complex relationships between the effects exerted by UVB rays on human skin and significantly improve the knowledge regarding the modulation of the early epidermal response induced by a single exposure to UVB in the presence of VVLe.

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Inside-out and outside-in organotypic normal human skin culture: JAK-STAT pathway is activated after pro-inflammatory psoriatic cytokine exposure

et al. 2022

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Evaluation of expression of Toll-Like Receptors 7 and 9, proliferation, and cytoskeletal biomarkers in plaque and guttate psoriasis: A pilot morphological study

Cited by 3 publications

References 23 publications

Th2 Cytokines Affect the Innate Immune Barrier without Impairing the Physical Barrier in a 3D Model of Normal Human Skin

Th2 Cytokines Affect the Innate Immune Barrier without Impairing the Physical Barrier in a 3D Model of Normal Human Skin

Keratin 17 as a Marker of UVB-Induced Stress in Human Epidermis and Modulation by <b><i>Vitis vinifera</i></b> Extract

Inside-out and outside-in organotypic normal human skin culture: JAK-STAT pathway is activated after pro-inflammatory psoriatic cytokine exposure

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