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Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms

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: closed (31 October 2022) | Viewed by 32884

Special Issue Editor

Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, 6020 Innsbruck, Austria
Interests: lipids; xenobiotic metabolism; PPAR; PXR mitochondria; peroxisomes; skin immunology; langerhans cells; atopic dermatitis
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Special Issue Information

Dear Colleagues,

Atopic dermatitis and psoriasis are two devastating, chronic and pruritic inflammatory skin diseases with high prevalence worldwide. Atopic dermatitis and psoriasis exhibit pathophysiological commonalities including impaired epidermal barrier, immune hyper-responsiveness, and local and systemic symptoms modulated by environmental factors such as the skin microbiota and stress. Moreover, they both have a strong genetic component. In the past few years, tremendous effort has been invested in research to make progress in understanding their underlying pathomechanisms. However, owing to their etiological complexity combined with the identification of several disease endotypes, we still do not understand how and why these diseases develop. The latest work has allowed deciphering in detail several important aspects of cellular and molecular abnormities involved in atopic dermatitis and psoriasis pathogenesis and has enabled the development of specific therapeutic strategies, namely, biologics. However, other therapeutic options might emerge from novel research going beyond the current paradigms. This Special Issue of IJMS welcomes a broad range of basic, preclinical and translational original and review articles focused on groundbreaking research in the field of both atopic dermatitis and psoriasis.

Prof. Dr. Sandrine Dubrac
Guest Editor

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Keywords

atopic dermatitis; psoriasis; pathogenesis; epidermal barrier; immune hyper-responsiveness; skin microbiota and stress

Published Papers (10 papers)

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Research

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14 pages, 2653 KiB  
Article
An Inflamed and Infected Reconstructed Human Epidermis to Study Atopic Dermatitis and Skin Care Ingredients
by Sébastien Cadau, Manon Gault, Nicolas Berthelemy, Chiung-Yueh Hsu, Louis Danoux, Nicolas Pelletier, Dominique Goudounèche, Carole Pons, Corinne Leprince, Valérie André-Frei, Michel Simon and Sabine Pain
Int. J. Mol. Sci. 2022, 23(21), 12880; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112880 - 25 Oct 2022
Cited by 5 | Viewed by 2328
Abstract
Atopic dermatitis (AD), the most common inflammatory skin disorder, is a multifactorial disease characterized by a genetic predisposition, epidermal barrier disruption, a strong T helper (Th) type 2 immune reaction to environmental antigens and an altered cutaneous microbiome. Microbial dysbiosis characterized by the [...] Read more.
Atopic dermatitis (AD), the most common inflammatory skin disorder, is a multifactorial disease characterized by a genetic predisposition, epidermal barrier disruption, a strong T helper (Th) type 2 immune reaction to environmental antigens and an altered cutaneous microbiome. Microbial dysbiosis characterized by the prevalence of Staphylococcus aureus (S. aureus) has been shown to exacerbate AD. In recent years, in vitro models of AD have been developed, but none of them reproduce all of the pathophysiological features. To better mimic AD, we developed reconstructed human epidermis (RHE) exposed to a Th2 pro-inflammatory cytokine cocktail and S. aureus. This model well reproduced some of the vicious loops involved in AD, with alterations at the physical, microbial and immune levels. Our results strongly suggest that S. aureus acquired a higher virulence potential when the epidermis was challenged with inflammatory cytokines, thus later contributing to the chronic inflammatory status. Furthermore, a topical application of a Castanea sativa extract was shown to prevent the apparition of the AD-like phenotype. It increased filaggrin, claudin-1 and loricrin expressions and controlled S. aureus by impairing its biofilm formation, enzymatic activities and inflammatory potential. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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19 pages, 4807 KiB  
Article
Ghrelin Represses Thymic Stromal Lymphopoietin Gene Expression through Activation of Glucocorticoid Receptor and Protein Kinase C Delta in Inflamed Skin Keratinocytes
by Hayan Jeong, Hyo-Jin Chong, Jangho So, Yejin Jo, Tae-Young Yune and Bong-Gun Ju
Int. J. Mol. Sci. 2022, 23(7), 3977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073977 - 02 Apr 2022
Cited by 1 | Viewed by 2516
Abstract
Ghrelin, a peptide hormone secreted from enteroendocrine cells of the gastrointestinal tract, has anti-inflammatory activity in skin diseases, including dermatitis and psoriasis. However, the molecular mechanism underlying the beneficial effect of ghrelin on skin inflammation is not clear. In this study, we found [...] Read more.
Ghrelin, a peptide hormone secreted from enteroendocrine cells of the gastrointestinal tract, has anti-inflammatory activity in skin diseases, including dermatitis and psoriasis. However, the molecular mechanism underlying the beneficial effect of ghrelin on skin inflammation is not clear. In this study, we found that ghrelin alleviates atopic dermatitis (AD)-phenotypes through suppression of thymic stromal lymphopoietin (TSLP) gene activation. Knockdown or antagonist treatment of growth hormone secretagogue receptor 1a (GHSR1a), the receptor for ghrelin, suppressed ghrelin-induced alleviation of AD-like phenotypes and suppression of TSLP gene activation. We further found that ghrelin induces activation of the glucocorticoid receptor (GR), leading to the binding of GR with histone deacetylase 3 (HDAC3) and nuclear receptor corepressor (NCoR) NCoR corepressor to negative glucocorticoid response element (nGRE) on the TSLP gene promoter. In addition, ghrelin-induced protein kinase C δ (PKCδ)-mediated phosphorylation of p300 at serine 89 (S89), which decreased the acetylation and DNA binding activity of nuclear factor- κB (NF-κB) p65 to the TSLP gene promoter. Knockdown of PKCδ abolished ghrelin-induced suppression of TSLP gene activation. Our study suggests that ghrelin may help to reduce skin inflammation through GR and PKCδ-p300-NF-κB-mediated suppression of TSLP gene activation. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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20 pages, 3648 KiB  
Article
Deacetylasperulosidic Acid Ameliorates Pruritus, Immune Imbalance, and Skin Barrier Dysfunction in 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis NC/Nga Mice
by Jin-Su Oh, Geum-Su Seong, Yong-Deok Kim and Se-Young Choung
Int. J. Mol. Sci. 2022, 23(1), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010226 - 25 Dec 2021
Cited by 8 | Viewed by 4531
Abstract
The prevalence of atopic dermatitis (AD), a disease characterized by severe pruritus, immune imbalance, and skin barrier dysfunction, is rapidly increasing worldwide. Deacetylasperulosidic acid (DAA) has anti-atopic activity in the three main cell types associated with AD: keratinocytes, mast cells, and eosinophils. Our [...] Read more.
The prevalence of atopic dermatitis (AD), a disease characterized by severe pruritus, immune imbalance, and skin barrier dysfunction, is rapidly increasing worldwide. Deacetylasperulosidic acid (DAA) has anti-atopic activity in the three main cell types associated with AD: keratinocytes, mast cells, and eosinophils. Our study investigated the anti-atopic activity of DAA in 2,4-dinitrochlorobenzene-induced NC/Nga mice. DAA alleviated the symptoms of AD, including infiltration of inflammatory cells (mast cells and eosinophils), epidermal thickness, ear thickness, and scratching behavior. Furthermore, DAA reduced serum IgE, histamine, and IgG1/IgG2a ratio and modulated the levels of AD-related cytokines and chemokines, namely interleukin (IL)-1β, IL-4, IL-6, IL-9, IL-10, IL-12, tumor necrosis factor-α, interferon-γ, thymic stromal lymphopoietin, thymus and activation-regulated chemokine, macrophage-derived chemokine, and regulated on activation the normal T cell expressed and secreted in the serum. DAA restored immune balance by regulating gene expression and secretion of Th1-, Th2-, Th9-, Th17-, and Th22-mediated inflammatory factors in the dorsal skin and splenocytes and restored skin barrier function by increasing the expression of the pro-filaggrin gene and barrier-related proteins filaggrin, involucrin, and loricrin. These results suggest DAA as a potential therapeutic agent that can alleviate the symptoms of AD by reducing pruritus, modulating immune imbalance, and restoring skin barrier function. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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15 pages, 3098 KiB  
Article
The Expression Pattern of Genes Related to Melanogenesis and Endogenous Opioids in Psoriasis
by Ulvi Loite, Liisi Raam, Ene Reimann, Paula Reemann, Ele Prans, Tanel Traks, Eero Vasar, Helgi Silm, Külli Kingo and Sulev Kõks
Int. J. Mol. Sci. 2021, 22(23), 13056; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313056 - 02 Dec 2021
Cited by 3 | Viewed by 1755
Abstract
The melanocortin system is a major regulator of stress responses in the skin and is responsible for the induction of melanin synthesis through activation of melanogenesis enzymes. The expression of both melanocortin system genes and melanogenesis enzyme genes is altered in psoriasis, and [...] Read more.
The melanocortin system is a major regulator of stress responses in the skin and is responsible for the induction of melanin synthesis through activation of melanogenesis enzymes. The expression of both melanocortin system genes and melanogenesis enzyme genes is altered in psoriasis, and the focus here was on twelve genes related to the signal transduction between them. Additionally, five endogenous opioid system genes that are involved in cutaneous inflammation were examined. Quantitative real-time-PCR was utilized to measure mRNA expression in punch biopsies from lesional and non-lesional skin of psoriasis patients and from the skin of healthy control subjects. Most of the genes related to melanogenesis were down-regulated in patients (CREB1, MITF, LEF1, USF1, MAPK14, ICAM1, PIK3CB, RPS6KB1, KIT, and ATRN). Conversely, an up-regulation occurred in the case of opioids (PENK, PDYN, and PNOC). The suppression of genes related to melanogenesis is in agreement with the reported reduction in pigmentation signaling in psoriatic skin and potentially results from the pro-inflammatory environment. The increase in endogenous opioids can be associated with their involvement in inflammatory dysregulation in psoriasis. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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17 pages, 15081 KiB  
Article
Aryl Hydrocarbon Receptor Repressor Is Hypomethylated in Psoriasis and Promotes Psoriasis-like Inflammation in HaCaT Cells
by Ji-Young Um, Bo-Young Chung, Han-Bi Kim, Jin-Cheol Kim, Chun-Wook Park and Hye-One Kim
Int. J. Mol. Sci. 2021, 22(23), 12715; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312715 - 24 Nov 2021
Cited by 4 | Viewed by 2168
Abstract
It is known that DNA hypomethylation of aryl hydrocarbon receptor repressor (AhRR), one of the epigenetic markers of environmental pollutants, causes skin diseases. However, the function and mechanisms are still unknown. We aimed to determine whether AhRR is hypomethylated in PBMC of psoriasis [...] Read more.
It is known that DNA hypomethylation of aryl hydrocarbon receptor repressor (AhRR), one of the epigenetic markers of environmental pollutants, causes skin diseases. However, the function and mechanisms are still unknown. We aimed to determine whether AhRR is hypomethylated in PBMC of psoriasis patients, as well as to examine the expression of psoriasis-related inflammatory cytokines and antimicrobial peptides after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment in HaCaT cells overexpressing or silencing AhRR. AhRR was determined by qPCR, Western blot, immunohistochemistry, and immunocytochemistry in skin tissue and HaCaT cells. DNA methylation of AhRR was performed by Infinium Human Methylation450 BeadChip in PBMC of psoriasis patients and methylation-specific PCR (MSP) in HaCaT cells. NF-κB pp50 translocation and activity were performed by immunocytochemistry and luciferase reporter assay, respectively. We verified AhRR gene expression in the epidermis from psoriasis patients and healthy controls. AhRR hypomethylation in PBMC of psoriasis patients and pAhRR-HaCaT cells was confirmed. The expression level of AhRR was increased in both TCDD-treated HaCaT cells and pAhRR-HaCaT cells. NF-κB pp50 translocation and activity increased with TCDD. Our results showed that AhRR was hypomethylated and overexpressed in the lesional skin of patients with psoriasis, thereby increasing AhRR gene expression and regulating pro-inflammatory cytokines through the NF-κB signaling pathway in TCDD-treated HaCaT cells. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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Review

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15 pages, 958 KiB  
Review
Transcriptional Basis of Psoriasis from Large Scale Gene Expression Studies: The Importance of Moving towards a Precision Medicine Approach
by Vidya S. Krishnan and Sulev Kõks
Int. J. Mol. Sci. 2022, 23(11), 6130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116130 - 30 May 2022
Cited by 8 | Viewed by 2594
Abstract
Transcriptome profiling techniques, such as microarrays and RNA sequencing (RNA-seq), are valuable tools for deciphering the regulatory network underlying psoriasis and have revealed large number of differentially expressed genes in lesional and non-lesional skin. Such approaches provide a more precise measurement of transcript [...] Read more.
Transcriptome profiling techniques, such as microarrays and RNA sequencing (RNA-seq), are valuable tools for deciphering the regulatory network underlying psoriasis and have revealed large number of differentially expressed genes in lesional and non-lesional skin. Such approaches provide a more precise measurement of transcript levels and their isoforms than any other methods. Large cohort transcriptomic analyses have greatly improved our understanding of the physiological and molecular mechanisms underlying disease pathogenesis and progression. Here, we mostly review the findings of some important large scale psoriatic transcriptomic studies, and the benefits of such studies in elucidating potential therapeutic targets and biomarkers for psoriasis treatment. We also emphasised the importance of looking into the alternatively spliced RNA isoforms/transcripts in psoriasis, rather than focussing only on the gene-level annotation. The neutrophil and blood transcriptome signature in psoriasis is also briefly reviewed, as it provides the immune status information of patients and is a less invasive platform. The application of precision medicine in current management of psoriasis, by combining transcriptomic data, improves the clinical response outcome in individual patients. Drugs tailored to individual patient’s genetic profile will greatly improve patient outcome and cost savings for the healthcare system. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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14 pages, 1238 KiB  
Review
Overlapping Features of Psoriasis and Atopic Dermatitis: From Genetics to Immunopathogenesis to Phenotypes
by Ya-Chu Tsai and Tsen-Fang Tsai
Int. J. Mol. Sci. 2022, 23(10), 5518; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105518 - 15 May 2022
Cited by 22 | Viewed by 5898
Abstract
Psoriasis (PSO) and atopic dermatitis (AD) were once considered to be mutually exclusive diseases, but gradually regarded as a spectrum of disease. Shared genetic loci of both diseases were noted in some populations, including Chinese. Shared immunopathogenesis involving Th17, Th1, Th22 cells, or [...] Read more.
Psoriasis (PSO) and atopic dermatitis (AD) were once considered to be mutually exclusive diseases, but gradually regarded as a spectrum of disease. Shared genetic loci of both diseases were noted in some populations, including Chinese. Shared immunopathogenesis involving Th17, Th1, Th22 cells, or even IL-13 was found in certain stages or phenotypes. This review discusses the overlapping genetic susceptibility, shared cytokines, immune-mediated comorbidities, and clinical presentations. Overlapping conditions could be classified into mainly PSO lesions with AD features or vice versa, concomitant PSO and AD, or disease transformation as a result of biologics treatment. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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17 pages, 8086 KiB  
Review
Annoying Psoriasis and Atopic Dermatitis: A Narrative Review
by Wei-Yu Chen, Shao-Chuan Chen, Shou-Yi Hsu, Yu-An Lin, Chun-Ming Shih, Chun-Yao Huang, Kuo-Hsien Wang and Ai-Wei Lee
Int. J. Mol. Sci. 2022, 23(9), 4898; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094898 - 28 Apr 2022
Cited by 14 | Viewed by 4086
Abstract
Skin is an important organ that mainly functions as a barrier. Skin diseases can damage a person’s self-confidence and reduce their willingness to socialize, as well as their social behavior and willingness. When the skin appearance is abnormal, in addition to affecting the [...] Read more.
Skin is an important organ that mainly functions as a barrier. Skin diseases can damage a person’s self-confidence and reduce their willingness to socialize, as well as their social behavior and willingness. When the skin appearance is abnormal, in addition to affecting the quality of life, it often leads to personal, social, and psychological dysfunction and even induces depression. Psoriasis and atopic dermatitis are common chronic skin diseases. Their prevalence in the world is 3–10%, and there is an increasing trend year by year. These congenital or acquired factors cause the dysfunction of the immune system and then destroy the barrier function of the skin. Because these patients are flooded with a variety of inflammatory mediators, this causes skin cells to be in chronic inflammation. Therefore, psoriasis and atopic dermatitis are also considered systemic chronic inflammatory diseases. In the healthcare systems of developed countries, it is unavoidable to spend high costs to relieve symptoms of psoriasis and atopic dermatitis patients, because psoriasis and atopic dermatitis have a great influence on individuals and society. Giving a lot of attention and developing effective treatment methods are the topics that the medical community must work on together. Therefore, we used a narrative review manuscript to discuss pathogenesis, clinical classification, incidence, and treatment options, including topical medication, systemic therapeutics, immunosuppressive medication for psoriasis, and atopic dermatitis, as well as also comparing the differences between these two diseases. We look forward to providing readers with comprehensive information on psoriasis and atopic dermatitis through this review article. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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42 pages, 1624 KiB  
Review
Opioidergic Signaling—A Neglected, Yet Potentially Important Player in Atopic Dermatitis
by Dorottya Ádám, József Arany, Kinga Fanni Tóth, Balázs István Tóth, Attila Gábor Szöllősi and Attila Oláh
Int. J. Mol. Sci. 2022, 23(8), 4140; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084140 - 08 Apr 2022
Cited by 5 | Viewed by 2773
Abstract
Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in [...] Read more.
Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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Other

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20 pages, 764 KiB  
Opinion
Psoriasis, Is It a Microdamage of Our “Sixth Sense”? A Neurocentric View
by Balázs Sonkodi
Int. J. Mol. Sci. 2022, 23(19), 11940; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911940 - 08 Oct 2022
Cited by 7 | Viewed by 2480
Abstract
Psoriasis is considered a multifactorial and heterogeneous systemic disease with many underlying pathologic mechanisms having been elucidated; however, the pathomechanism is far from entirely known. This opinion article will demonstrate the potential relevance of the somatosensory Piezo2 microinjury-induced quad-phasic non-contact injury model in [...] Read more.
Psoriasis is considered a multifactorial and heterogeneous systemic disease with many underlying pathologic mechanisms having been elucidated; however, the pathomechanism is far from entirely known. This opinion article will demonstrate the potential relevance of the somatosensory Piezo2 microinjury-induced quad-phasic non-contact injury model in psoriasis through a multidisciplinary approach. The primary injury is suggested to be on the Piezo2-containing somatosensory afferent terminals in the Merkel cell–neurite complex, with the concomitant impairment of glutamate vesicular release machinery in Merkel cells. Part of the theory is that the Merkel cell–neurite complex contributes to proprioception; hence, to the stretch of the skin. Piezo2 channelopathy could result in the imbalanced control of Piezo1 on keratinocytes in a clustered manner, leading to dysregulated keratinocyte proliferation and differentiation. Furthermore, the author proposes the role of mtHsp70 leakage from damaged mitochondria through somatosensory terminals in the initiation of autoimmune and autoinflammatory processes in psoriasis. The secondary phase is harsher epidermal tissue damage due to the primary impaired proprioception. The third injury phase refers to re-injury and sensitization with the derailment of healing to a state when part of the wound healing is permanently kept alive due to genetical predisposition and environmental risk factors. Finally, the quadric damage phase is associated with the aging process and associated inflammaging. In summary, this opinion piece postulates that the primary microinjury of our “sixth sense”, or the Piezo2 channelopathy of the somatosensory terminals contributing to proprioception, could be the principal gateway to pathology due to the encroachment of our preprogrammed genetic encoding. Full article
(This article belongs to the Special Issue Atopic Dermatitis and Psoriasis Pathogenesis: Going beyond Paradigms)
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