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Molecular and Cellular Mechanisms of Skin Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 January 2025 | Viewed by 10528

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Dr. Elisabetta Palazzo

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Guest Editor

DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
Interests: skin cancer; squamous cell carcinoma; psoriasis; epidermal homeostasis; keratinocyte stem cells; epidermal differentiation; skin inflammation; mouse models; zebrafish models; in vitro skin 3D model; skin tumor spheroids; next-generation sequencing
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Special Issue Information

Dear Colleagues,

In recent years, enormous progress has been made in providing a thorough characterization of dermatological diseases at both molecular and cellular levels, and it is due to the identification of new molecular mechanisms and increasingly technological experimental approaches used for their study.

In particular, the detailed analysis of cell metabolism, proliferation, and differentiation has allowed us to define more accurately cell populations with specific functions, both in the health and pathological contexts. Moreover, the development of new technologies, including NGS and gene editing methods, allows us to decipher the necessary information for obtaining concrete applications for the therapeutical responses that each skin disease needs.

Considering the above facts, this Special Issue is open to research papers, up-to-date review articles, and commentaries, related to novel insights into healthy and pathological skin cell and tissue biology, including metabolomic, transcriptomic, or proteomic aspects, and inflammation. The use of novel tools, both in vitro and in vivo, such as a three-dimensional approach, is encouraged.

Dr. Elisabetta Palazzo
Guest Editor

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Keywords

hyperproliferative skin diseases
psoriasis
keratinocyte carcinoma
actinic keratosis
atopic dermatitis
skin inflammation
inflammation-associated skin diseases
epidermal differentiation
epidermal cell metabolism
3D models
in vivo models

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Published Papers (9 papers)

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Research

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25 pages, 7716 KiB

Open AccessArticle

The Expression of Cytokines and Chemokines Potentially Distinguishes Mild and Severe Psoriatic Non-Lesional and Resolved Skin from Healthy Skin and Indicates Different Stages of Inflammation

by Renáta Bozó, Lili Borbála Flink, Barbara Ambrus, Ameneh Ghaffarinia, Balázs Koncz, Róbert Kui, Rolland Gyulai, Lajos Kemény and Zsuzsanna Bata-Csörgő

Int. J. Mol. Sci. 2024, 25(20), 11292; https://doi.org/10.3390/ijms252011292 - 20 Oct 2024

Viewed by 1073

Abstract

In the psoriatic non-lesional (PS-NL) skin, the tissue environment potentially influences the development and recurrence of lesions. Therefore, we aimed to investigate mechanisms involved in regulating tissue organization in PS-NL skin. Cytokine, chemokine, protease, and protease inhibitor levels were compared between PS-NL skin of patients with mild and severe symptoms and healthy skin. By comparing mild and severe PS-NL vs. healthy skin, differentially expressed cytokines and chemokines suggested alterations in hemostasis-related processes, while protease inhibitors showed no psoriasis severity-related changes. Comparing severe and mild PS-NL skin revealed disease severity-related changes in the expression of proteases, cytokines, and chemokines primarily involving methyl-CpG binding protein 2 (MECP2) and extracellular matrix organization-related mechanisms. Cytokine and chemokine expression in clinically resolved versus healthy skin showed slight interleukin activity, differing from patterns in mild and severe PS-NL skin. Immunofluorescence analysis revealed the severity-dependent nuclear expression pattern of MECP2 and decreased expression of 5-methylcytosine and 5-hydroxymethylcytosine in the PS-NL vs. healthy skin, and in resolved vs. healthy skin. Our results suggest distinct cytokine–chemokine signaling between the resolved and PS-NL skin of untreated patients with varying severities. These results highlight an altered inflammatory response, epigenetic regulation, and tissue organization in different types of PS-NL skin with possibly distinct, severity-dependent para-inflammatory states. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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12 pages, 1592 KiB

Open AccessArticle

The Expression of Vitamin D Receptor on Peripheral Blood Mononuclear Cells in Patients with Psoriasis

by Azin Jasmin Zanghaneh, Andrea Elmelid, Martin Gillstedt, Omar Ahmic, Bengt Andersson and Amra Osmancevic

Int. J. Mol. Sci. 2024, 25(19), 10677; https://doi.org/10.3390/ijms251910677 - 3 Oct 2024

Viewed by 883

Abstract

Vitamin D plays an important role in psoriasis, but its involvement in pathogenesis remains unclear. This study aimed to evaluate vitamin D receptor (VDR) expression on peripheral blood mononuclear cells (PBMCs) in patients with psoriasis and healthy controls and to study the effects of the Etanercept treatment on VDR expression on PBMCs in patients with psoriasis. Twenty patients with moderate to severe psoriasis received treatment with Etanercept for 24 weeks. The age- and sex-matched controls did not receive any intervention. VDR expression on CD3⁺ lymphocytes and CD14⁺ monocytes, and serum levels of total and free 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)₂D) were analyzed at baseline, after 10–12 weeks, and after 24 weeks in both groups. VDR expression was analyzed using flow cytometry. We observed higher expression of the VDR on CD14⁺ monocytes in psoriasis patients compared to healthy controls at baseline. This difference was no longer significant after 24 weeks of the Etanercept treatment. The patients with psoriasis improved clinically. However, VDR expression was unaltered during the Etanercept treatment, and there was no correlation between VDR expression and disease severity. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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13 pages, 1814 KiB

Open AccessArticle

shRNA-Targeting Caspase-3 Inhibits Cell Detachment Induced by Pemphigus Vulgaris Autoantibodies in HaCaT Cells

by Deyanira Pacheco-Tovar, María-Guadalupe Pacheco-Tovar, Santiago Saavedra-Alonso, Pablo Zapata-Benavides, Felipe-de-Jesús Torres-del-Muro, Juan-José Bollain-y-Goytia, Rafael Herrera-Esparza, Cristina Rodríguez-Padilla and Esperanza Avalos-Díaz

Int. J. Mol. Sci. 2024, 25(16), 8864; https://doi.org/10.3390/ijms25168864 - 14 Aug 2024

Viewed by 773

Abstract

Pemphigus is an autoimmune disease that affects the skin and mucous membranes, induced by the deposition of pemphigus IgG, which mainly targets desmogleins 1 and 3 (Dsg1 and 3). This autoantibody causes steric interference between Dsg1 and 3 and the loss of cell adhesion, producing acantholysis. This molecule and its cellular effects are clinically reflected as intraepidermal blistering. Pemphigus vulgaris-IgG (PV-IgG) binding involves p38MAPK-signaling-dependent caspase-3 activation. The present work assessed the in vitro effect of PV-IgG on the adherence of HaCaT cells dependent on caspase-3. PV-IgG induced cell detachment and apoptotic changes, as demonstrated by annexin fluorescent assays. The effect of caspase-3 induced by PV-IgG was suppressed in cells pre-treated with caspase-3-shRNA, and normal IgG (N-IgG) as a control had no relevant effects on the aforementioned parameters. The results demonstrated that shRNA reduces caspase-3 expression, as measured via qRT-PCR and via Western blot and immunofluorescence, and increases cell adhesion. In conclusion, shRNA prevented in vitro cell detachment and the late effects of apoptosis induced by PV-IgG on HaCaT cells, furthering our understanding of the molecular role of caspase-3 cell adhesion dependence in pemphigus disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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14 pages, 1804 KiB

Open AccessArticle

ABCC1 Is a ΔNp63 Target Gene Overexpressed in Squamous Cell Carcinoma

by Veronica La Banca, Sara De Domenico, Sara Nicolai, Veronica Gatti, Stefano Scalera, Marcello Maugeri, Alessandro Mauriello, Manuela Montanaro, Jens Pahnke, Eleonora Candi, Silvia D’Amico and Angelo Peschiaroli

Int. J. Mol. Sci. 2024, 25(16), 8741; https://doi.org/10.3390/ijms25168741 - 10 Aug 2024

Viewed by 1004

Abstract

The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member ABCC1 as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the ABCC1 gene locus. In cutaneous SCC and during the activation of the keratinocyte differentiation program, ∆Np63 and ABCC1 levels are positively correlated raising the possibility that ABCC1 might be involved in the regulation of the proliferative/differentiative capabilities of squamous tissue. However, we did not find any gross alteration in the structure and morphology of the epidermis in humanized hABCC1 knock-out mice. Conversely, we found that the genetic ablation of ABCC1 led to a marked reduction in inflammation-mediated proliferation of keratinocytes, suggesting that ABCC1 might be involved in the regulation of keratinocyte proliferation upon inflammatory/proliferative signals. In line with these observations, we found a significant increase in ABCC1 expression in squamous cell carcinomas (SCCs), a tumor type characterized by keratinocyte hyper-proliferation and a pro-inflammatory tumor microenvironment. Collectively, these data uncover ABCC1 as an additional ∆Np63 target gene potentially involved in those skin diseases characterized by dysregulation of proliferation/differentiation balance. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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8 pages, 689 KiB

Open AccessCommunication

Interleukin Profiling in Atopic Dermatitis and Chronic Nodular Prurigo

by Henning Wiegmann, Lina Renkhold, Claudia Zeidler, Konstantin Agelopoulos and Sonja Ständer

Int. J. Mol. Sci. 2024, 25(15), 8445; https://doi.org/10.3390/ijms25158445 - 2 Aug 2024

Viewed by 1393

Abstract

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production—particularly IL-4/13—are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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18 pages, 16517 KiB

Open AccessArticle

Therapeutic Effect of Lecigel, Cetiol^®CC, Activonol-6, Activonol-M, 1,3-Propanediol, Soline, and Fucocert^® (LCAA-PSF) Treatment on Imiquimod-Induced Psoriasis-like Skin in Mice

by Chih-Ching Li, Chih-Chien Lin, Chun-Yi Lee, Meei-Ling Sheu, Yi-Ching Tsai, Chia-Yun Tsai, Hao-Ting Wu, Ren-Jang Wu and De-Wei Lai

Int. J. Mol. Sci. 2024, 25(14), 7720; https://doi.org/10.3390/ijms25147720 - 14 Jul 2024

Viewed by 1494

Abstract

The individual ingredients of 1,3-Propanediol, Soline, and Fucocert^® (PSF) are often used as cosmetic formulations in skin care. In addition, the mixture of Lecigel, Cetiol^®CC, Activonol-6, and Activonol-M (LCAA) is often used as a cosmetic base. However, whether the combination of LCAA with PSF (LCAA-PSF) exerts a therapeutic effect on psoriasis remains unclear. In this study, mice induced with imiquimod (IMQ) were divided into three groups and administered 100 mg/day of LCAA, 100 mg/day of LCAA-PSF, or Vaseline on the dorsal skin of each mouse. Weight-matched mice treated with Vaseline alone were used as controls. Hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay(ELISA) were used to assess tissue morphology and inflammatory cytokines. RNA sequencing analysis was used to predict the mechanism underlying the action of LCAA-PSF against psoriasis, while immunohistochemical analysis validation was used to identify pertinent molecular pathways. The results demonstrated that LCAA-PSF alleviated IMQ-induced keratinocyte differentiation/ proliferation bydecreasingthe serum levels of inflammatory cytokines such as IL-6, TNF-α, IL-23, and IL-17A and the epidermisof TGFβ, Ki67, CK5/6, and VEGF expression, which is associated with angiogenesis and keratinocyte differentiation/ proliferation. These findings highlight the antipsoriatic activity of LCAA-PSF in a psoriasis-like mouse model and suggest this may occurvia the inhibition of inflammatory factor secretionand the TGFβ-related signal pathway. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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Review

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24 pages, 2197 KiB

Open AccessReview

Psoriasis and Seasonality: Exploring the Genetic and Epigenetic Interactions

by Michał Niedźwiedź, Małgorzata Skibińska, Magdalena Ciążyńska, Marcin Noweta, Agnieszka Czerwińska, Janusz Krzyścin, Joanna Narbutt and Aleksandra Lesiak

Int. J. Mol. Sci. 2024, 25(21), 11670; https://doi.org/10.3390/ijms252111670 - 30 Oct 2024

Viewed by 845

Abstract

Psoriasis is a multifactorial, chronic, and inflammatory disease that severely impacts patients’ quality of life. The disease is caused by genetic irregularities affected by epigenetic and environmental factors. Some of these factors may include seasonal changes, such as solar radiation, air pollution, and humidity, and changes in circadian rhythm, especially in the temporal and polar zones. Thus, some psoriasis patients report seasonal variability of symptoms. Through a comprehensive review, we aim to delve deeper into the intricate interplay between seasonality, environmental factors, and the genetic and epigenetic landscape of psoriasis. By elucidating these complex relationships, we strive to provide insights that may inform targeted interventions and personalized management strategies for individuals living with psoriasis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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19 pages, 1059 KiB

Open AccessReview

Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives

by Mbarka Bchetnia, Julie Powell, Catherine McCuaig, Anne-Marie Boucher-Lafleur, Charles Morin, Audrey Dupéré and Catherine Laprise

Int. J. Mol. Sci. 2024, 25(17), 9495; https://doi.org/10.3390/ijms25179495 - 31 Aug 2024

Viewed by 1248

Abstract

Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma. The simplex form (EBS) is characterized by recurrent blister formation within the basal layer of the epidermis. It most often results from dominant mutations in the genes coding for keratin (K) 5 or 14 proteins (KRT5 and KRT14). A disruptive mutation in KRT5 or KRT14 will not only structurally impair the cytoskeleton, but it will also activate a cascade of biochemical mechanisms contributing to EBS. Skin lesions are painful and disfiguring and have a significant impact on life quality. Several gene expression studies were accomplished on mouse model and human keratinocytes to define the gene expression signature of EBS. Several key genes associated with EBS were identified as specific immunological mediators, keratins, and cell junction components. These data deepened the understanding of the EBS pathophysiology and revealed important functional biological processes, particularly inflammation. This review emphasizes the three EBS subtypes caused by dominant mutations on either KRT5 or KRT14 (localized, intermediate, and severe). It aims to summarize current knowledge about the EBS expression profiling pattern and predicted molecular mechanisms involved and to outline progress in therapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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Other

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7 pages, 1864 KiB

Open AccessBrief Report

Unbiased Proteomic Exploration Suggests Overexpression of Complement Cascade Proteins in Plasma from Patients with Psoriasis Compared with Healthy Individuals

by Bjørn Kromann, Lili Niu, Line B. P. Møller, Julie Sølberg, Karolina Sulek, Mette Gyldenløve, Beatrice Dyring-Andersen, Lone Skov and Marianne B. Løvendorf

Int. J. Mol. Sci. 2024, 25(16), 8791; https://doi.org/10.3390/ijms25168791 - 13 Aug 2024

Viewed by 824

Abstract

Knowledge about the molecular mechanisms underlying the systemic inflammation observed in psoriasis remains incomplete. In this study, we applied mass spectrometry-based proteomics to compare the plasma protein levels between patients with psoriasis and healthy individuals, aiming to unveil potential systemically dysregulated proteins and pathways associated with the disease. Plasma samples from adult patients with moderate-to-severe psoriasis vulgaris (N = 59) and healthy age- and sex-matched individuals (N = 21) were analyzed using liquid chromatography–tandem mass spectrometry. Patients did not receive systemic anti-psoriatic treatment for four weeks before inclusion. A total of 776 protein groups were quantified. Of these, 691 were present in at least 60% of the samples, providing the basis for the downstream analysis. We identified 20 upregulated and 22 downregulated proteins in patients with psoriasis compared to controls (p < 0.05). Multiple proteins from the complement system were upregulated, including C2, C4b, C5, and C9, and pathway analysis revealed enrichment of proteins involved in complement activation and formation of the terminal complement complex. On the other end of the spectrum, periostin was the most downregulated protein in sera from patients with psoriasis. This comprehensive proteomic investigation revealed significantly elevated levels of complement cascade proteins in psoriatic plasma, which might contribute to increased systemic inflammation in patients with psoriasis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Skin Diseases)

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