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Functional Defects of Keratinocytes in Inflammatory 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 "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 29958

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Dr. Paola Maura Ticarico

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Guest Editor

Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Via dell’Istria 65/1, 34137 Trieste, Italy
Interests: cell biology; apoptosis; keratinocytes; keratinocytes differentiation; keratinocytes proliferation; notch signaling; dermatology diseases
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Sergio Crovella

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Co-Guest Editor

1. Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy
2. Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar
Interests: immunology; clinical pathology; molecular genetics; molecular biology; OMICs; bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In addition to providing physical, chemical and biological protection against the external environment, the skin barrier is important for maintaining homeostasis by preventing an excessive loss of water, ions and serum proteins.

Keratinocytes are the main cell type of the epidermis and originate in the basal layer, in which keratinocytes are mitotically active; then, they progressively differentiate and migrate upwards to the stratum corneum. Moreover, keratinocytes actively contribute in the cutaneous immune responses producing a plethora of inflammatory mediators.

Defects in keratinocytes differentiation, proliferation and inflammation are closely related to many inflammatory skin diseases, such as Hidradenitis Suppurativa, Psoriasis, Atopic Dermatitis and Behçet disease.

In this context, Notch signaling plays a key role mediating the normal keratinocytes turnover. Notch signaling controls the induction of keratinocytes growth, promotes activation of the differentiation program, and also it is involved in the regulation of inflammatory responses. Alterations of Notch signaling can induce a failure in the regulation of keratinocytes functions, which in turn produces skin diseases.

This Special Issue is dedicated to the role of keratinocytes in skin diseases. Areas of particular interest include, but are not limited to, keratinization and skin diseases, autoinflammatory keratinization diseases, and Notch signaling regulation in skin diseases.

Dr. Paola Maura Ticarico
Guest Editor
Prof. Dr. Sergio Crovella
Co-Guest Editor

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Keywords

dermatological diseases
notch signaling
keratinocytes
inflammation
autoinflammation
differentiation
keratinization
proliferation

Published Papers (7 papers)

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Research

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16 pages, 5017 KiB

Open AccessArticle

Lysophosphatidic Acid Mediates Imiquimod-Induced Psoriasis-like Symptoms by Promoting Keratinocyte Proliferation through LPAR1/ROCK2/PI3K/AKT Signaling Pathway

by Donghee Kim, Hyo-Jin Kim, Jin-Ok Baek, Joo-Young Roh and Hee-Sook Jun

Int. J. Mol. Sci. 2021, 22(19), 10777; https://doi.org/10.3390/ijms221910777 - 05 Oct 2021

Cited by 17 | Viewed by 3710

Abstract

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27^Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27^Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

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12 pages, 2729 KiB

Open AccessArticle

Proteoglycan Combined with Hyaluronic Acid and Hydrolyzed Collagen Restores the Skin Barrier in Mild Atopic Dermatitis and Dry, Eczema-Prone Skin: A Pilot Study

by Young In Lee, Sang Gyu Lee, Jemin Kim, Sooyeon Choi, Inhee Jung and Ju Hee Lee

Int. J. Mol. Sci. 2021, 22(19), 10189; https://doi.org/10.3390/ijms221910189 - 22 Sep 2021

Cited by 13 | Viewed by 4064

Abstract

Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus. Here, we investigated the effects of a novel emollient containing H.ECM^TM liposome, which contains a soluble proteoglycan in combination with hydrolyzed collagen and hyaluronic acid. A prospective, single-arm study was conducted on 25 participants with mild atopic dermatitis or dry skin to assess the hydration and anti-inflammatory effect of the novel emollient applied daily over four weeks. All efficacy parameters, including itching severity, transepidermal water loss, and skin hydration, improved significantly after four weeks. The in vitro and ex vivo studies confirmed the restoration of the skin’s barrier function. The study revealed the clinical and laboratory efficacy of H.ECM^TM liposome in reducing itching and improving the skin’s barrier integrity. Thus, the use of H.ECM^TM liposome can be considered a therapeutic option for dry and eczema-prone skin. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

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Review

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19 pages, 1927 KiB

Open AccessReview

Epigenetic Mechanisms of Epidermal Differentiation

by Chiara Moltrasio, Maurizio Romagnuolo and Angelo Valerio Marzano

Int. J. Mol. Sci. 2022, 23(9), 4874; https://doi.org/10.3390/ijms23094874 - 28 Apr 2022

Cited by 24 | Viewed by 2984

Abstract

Keratinocyte differentiation is an essential process for epidermal stratification and stratum corneum formation. Keratinocytes proliferate in the basal layer of the epidermis and start their differentiation by changing their functional or phenotypical type; this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes that play a pivotal role in epidermal development. Epidermal development and the keratinocyte differentiation program are orchestrated by several transcription factors, signaling pathways, and epigenetic regulators. The latter exhibits both activating and repressive effects on chromatin in keratinocytes via the ATP-dependent chromatin remodelers, histone demethylases, and genome organizers that promote terminal keratinocyte differentiation, and the DNA methyltransferases, histone deacetylases, and Polycomb components that stimulate proliferation of progenitor cells and inhibit premature activation of terminal differentiation-associated genes. In addition, microRNAs are involved in different processes between proliferation and differentiation during the program of epidermal development. Here, we bring together current knowledge of the mechanisms controlling gene expression during keratinocyte differentiation. An awareness of epigenetic mechanisms and their alterations in health and disease will help to bridge the gap between our current knowledge and potential applications for epigenetic regulators in clinical practice to pave the way for promising target therapies. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

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19 pages, 15440 KiB

Open AccessReview

Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases

by Paola Maura Tricarico, Donatella Mentino, Aurora De Marco, Cecilia Del Vecchio, Sabino Garra, Gerardo Cazzato, Caterina Foti, Sergio Crovella and Giuseppe Calamita

Int. J. Mol. Sci. 2022, 23(7), 4020; https://doi.org/10.3390/ijms23074020 - 05 Apr 2022

Cited by 16 | Viewed by 6333

Abstract

The skin is the largest organ of the human body, serving as an effective mechanical barrier between the internal milieu and the external environment. The skin is widely considered the first-line defence of the body, with an essential function in rejecting pathogens and preventing mechanical, chemical, and physical damages. Keratinocytes are the predominant cells of the outer skin layer, the epidermis, which acts as a mechanical and water-permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. During this migration process, keratinocytes undertake a differentiation program known as keratinization process. Dysregulation of this differentiation process can result in a series of skin disorders. In this context, aquaporins (AQPs), a family of membrane channel proteins allowing the movement of water and small neutral solutes, are emerging as important players in skin physiology and skin diseases. Here, we review the role of AQPs in skin keratinization, hydration, keratinocytes proliferation, water retention, barrier repair, wound healing, and immune response activation. We also discuss the dysregulated involvement of AQPs in some common inflammatory dermatological diseases characterised by skin barrier disruption. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

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19 pages, 2060 KiB

Open AccessReview

Unraveling the Role of Sex Hormones on Keratinocyte Functions in Human Inflammatory Skin Diseases

by Rossella Gratton, Cecilia Del Vecchio, Luisa Zupin and Sergio Crovella

Int. J. Mol. Sci. 2022, 23(6), 3132; https://doi.org/10.3390/ijms23063132 - 15 Mar 2022

Cited by 17 | Viewed by 4339

Abstract

The skin exerts several fundamental functions that are the first physical, chemical and immune barriers to the human body. Keratinocytes, the main cell type of the epidermis, provide mechanical defense, support skin integrity and actively endorse cutaneous immune responses. Not surprisingly, considering these crucial activities, alterations in keratinocyte functions are associated with different inflammatory skin diseases. Recent findings indicate that the skin should not only be regarded as a target for hormones but that it should also be considered as an endocrine peripheral organ that is directly involved in the synthesis and metabolism of these chemical messengers. Sex hormones have multiple effects on the skin, attributed to the binding with intracellular receptors expressed by different skin cell populations, including keratinocytes, that activate downstream signaling routes that modulate specific cellular functions and activities. This review is aimed at reorganizing the current knowledge on the role exerted by sex hormones on keratinocyte function in five different inflammatory skin diseases: Hidradenitis suppurativa; Acne vulgaris; Atopic dermatitis; progesterone hypersensitivity; psoriasis. The results of our work aim to provide a deeper insight into common cellular mechanisms and molecular effectors that might constitute putative targets to address for the development of specific therapeutic interventions. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

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32 pages, 484 KiB

Open AccessReview

The Modulatory Influence of Plant-Derived Compounds on Human Keratinocyte Function

by Anna Merecz-Sadowska, Przemysław Sitarek, Karolina Zajdel, Ewa Kucharska, Tomasz Kowalczyk and Radosław Zajdel

Int. J. Mol. Sci. 2021, 22(22), 12488; https://doi.org/10.3390/ijms222212488 - 19 Nov 2021

Cited by 5 | Viewed by 2655

Abstract

The plant kingdom is a rich source of secondary metabolites with numerous properties, including the potential to modify keratinocyte biology. Keratinocytes are important epithelial cells that play a protective role against various chemical, physical and biological stimuli, and participate in reactive oxygen scavenging and inflammation and wound healing processes. The epidermal cell response may be modulated by phytochemicals via changes in signal transduction pathways. Plant extracts and single secondary compounds can possess a high antioxidant capacity and may suppress reactive oxygen species release, inhibit pro-apoptotic proteins and apoptosis and activate antioxidant enzymes in keratinocytes. Moreover, selected plant extracts and single compounds also exhibit anti-inflammatory properties and exposure may result in limited production of adhesion molecules, pro-inflammatory cytokines and chemokines in keratinocytes. In addition, plant extracts and single compounds may promote keratinocyte motility and proliferation via the regulation of growth factor production and enhance wound healing. While such plant compounds may modulate keratinocyte functions, further in vitro and in vivo studies are needed on their mechanisms of action, and more specific toxicity and clinical studies are needed to ensure their effectiveness and safety for use on human skin. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

35 pages, 1874 KiB

Open AccessReview

Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex

by Nadezhda A. Evtushenko, Arkadii K. Beilin, Anastasiya V. Kosykh, Ekaterina A. Vorotelyak and Nadya G. Gurskaya

Int. J. Mol. Sci. 2021, 22(22), 12446; https://doi.org/10.3390/ijms222212446 - 18 Nov 2021

Cited by 15 | Viewed by 4412

Abstract

Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures. The cellular pathology of most EBS subtypes is associated with the fragility of the intermediate filament network, cytolysis of the basal layer of the epidermis, or attenuation of hemidesmosomal/desmosomal components. Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes. Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs. Global changes in cellular signaling mainly occur in cases of severe dominant EBS mutations. The spectrum of changes initiated by phosphorylation includes the inhibition of proteasome degradation, TNF-α signaling activation, deregulated proliferation, abnormal cell migration, and impaired adherence of keratinocytes. ER stress also leads to the release of proinflammatory danger-associated molecular pattern (DAMP) molecules, which enhance avalanche-like inflammation. Many instances of positive feedback in the course of cellular stress and the development of sterile inflammation led to systemic chronic inflammation in EBS. This highlights the role of keratin in the maintenance of epidermal and immune homeostasis. Full article

(This article belongs to the Special Issue Functional Defects of Keratinocytes in Inflammatory Skin Diseases)

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