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Nakajima S, Nakamizo S, Nomura T, Ishida Y, Sawada Y, Kabashima K. Integrating multi-omics approaches in deciphering atopic dermatitis pathogenesis and future therapeutic directions. Allergy 2024; 79:2366-2379. [PMID: 38837434 DOI: 10.1111/all.16183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/23/2024] [Accepted: 05/24/2024] [Indexed: 06/07/2024]
Abstract
Atopic dermatitis (AD), a complex and heterogeneous chronic inflammatory skin disorder, manifests in a spectrum of clinical subtypes. The application of genomics has elucidated the role of genetic variations in predisposing individuals to AD. Transcriptomics, analyzing gene expression alterations, sheds light on the molecular underpinnings of AD. Proteomics explores the involvement of proteins in AD pathophysiology, while epigenomics examines the impact of environmental factors on gene expression. Lipidomics, which investigates lipid profiles, enhances our understanding of skin barrier functionalities and their perturbations in AD. This review synthesizes insights from these omics approaches, highlighting their collective importance in unraveling the intricate pathogenesis of AD. The review culminates by projecting future trajectories in AD research, particularly the promise of multi-omics in forging personalized medicine and novel therapeutic interventions. Such an integrated multi-omics strategy is poised to transform AD comprehension and management, steering towards more precise and efficacious treatment modalities.
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Affiliation(s)
- Saeko Nakajima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Drug Discovery for Inflammatory Skin Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoshi Nakamizo
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takashi Nomura
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Drug Development for Intractable Diseases, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Ishida
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yu Sawada
- Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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2
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Blaess M, Csuk R, Schätzl T, Deigner HP. Elongation of Very Long-Chain Fatty Acids (ELOVL) in Atopic Dermatitis and the Cutaneous Adverse Effect AGEP of Drugs. Int J Mol Sci 2024; 25:9344. [PMID: 39273293 PMCID: PMC11395647 DOI: 10.3390/ijms25179344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/15/2024] Open
Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease, in particular among infants, and is characterized, among other things, by a modification in fatty acid and ceramide composition of the skin's stratum corneum. Palmitic acid and stearic acid, along with C16-ceramide and 2-hydroxy C16-ceramide, occur strikingly in AD. They coincide with a simultaneous decrease in very long-chain ceramides and ultra-long-chain ceramides, which form the outermost lipid barrier. Ceramides originate from cellular sphingolipid/ceramide metabolism, comprising a well-orchestrated network of enzymes involving various ELOVLs and CerSs in the de novo ceramide synthesis and neutral and acid CERase in degradation. Contrasting changes in long-chain ceramides and very long-chain ceramides in AD can be more clearly explained by the compartmentalization of ceramide synthesis. According to our hypothesis, the origin of increased C16-ceramide and 2-hydroxy C16-ceramide is located in the lysosome. Conversely, the decreased ultra-long-chain and very long-chain ceramides are the result of impaired ELOVL fatty acid elongation. The suggested model's key elements include the lysosomal aCERase, which has pH-dependent long-chain C16-ceramide synthase activity (revaCERase); the NADPH-activated step-in enzyme ELOVL6 for fatty acid elongation; and the coincidence of impaired ELOVL fatty acid elongation and an elevated lysosomal pH, which is considered to be the trigger for the altered ceramide biosynthesis in the lysosome. To maintain the ELOVL6 fatty acid elongation and the supply of NADPH and ATP to the cell, the polyunsaturated PPARG activator linoleic acid is considered to be one of the most suitable compounds. In the event that the increase in lysosomal pH is triggered by lysosomotropic compounds, compounds that disrupt the transmembrane proton gradient or force the breakdown of lysosomal proton pumps, non-HLA-classified AGEP may result.
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Affiliation(s)
- Markus Blaess
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany
| | - René Csuk
- Organic Chemistry, Martin-Luther University Halle-Wittenberg, Kurt-Mothes, Str. 2, D-06120 Halle (Saale), Germany
| | - Teresa Schätzl
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany
| | - Hans-Peter Deigner
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany
- Fraunhofer Institute IZI, Leipzig, EXIM Department, Schillingallee 68, D-18057 Rostock, Germany
- Faculty of Science, Tuebingen University, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany
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Sashikawa-Kimura M, Takada M, Hossain MR, Tsuda H, Xie X, Komine M, Ohtsuki M, Imokawa G. Overexpression of the β-Subunit of Acid Ceramidase in the Epidermis of Mice Provokes Atopic Dermatitis-like Skin Symptoms. Int J Mol Sci 2024; 25:8737. [PMID: 39201426 PMCID: PMC11354809 DOI: 10.3390/ijms25168737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/30/2024] [Accepted: 08/08/2024] [Indexed: 09/02/2024] Open
Abstract
We previously reported that a pathogenic abnormality in the barrier and water-holding functions of the stratum corneum (SC) in the skin of patients with atopic dermatitis (AD) is mainly attributable to significantly decreased levels of total ceramides in the SC. That decrease is mediated by the abnormal expression of a novel ceramide-reducing enzyme, sphingomyelin/glucosylceramide deacylase (SGDase), which is the β-subunit (ASAH1b) of acid ceramidase. In this study, we determined whether mice overexpressing ASAH1b in their epidermis develop AD-like skin symptoms. We generated transgenic (TG) mice overexpressing ASAH1b, regulated by the involucrin promoter, to localize its expression in the upper epidermis. After hair removal using a depilatory cream containing glycolic acid, the TG mice without any visible skin inflammation at 8 weeks of age had increased levels of ASAH1b and decreased levels of SC ceramide, with disrupted barrier functions measured by trans-epidermal water loss compared to the wild-type (WT) mice. Interestingly, enzymatic assays revealed that SGDase activity was not detectable in the skin of the TG mice compared to WT mice. Immunological staining revealed that there was an increased expression level of IL-33 in the epidermis and an accumulation of macrophages in the dermis of TG mice compared to WT mice, which are phenotypic characteristics of AD, that were exacerbated by tape-stripping of the skin. In the skin of the TG mice, the mRNA levels of IL-5, CCL11, IL-22, CXCL10, and IFNγ were significantly upregulated compared to the WT mice, and tape-stripping significantly increased the mRNA levels of IL-4, IL-33, CXCL1, CXCL12, TLR9, and CD163 compared to WT mice. These findings strongly indicate that the skin of the depilatory cream-treated TG mice exists in an atopic dry skin condition that is highly sensitive to various environmental stimuli. The sum of our results suggests that ASAH1b itself, even in the absence of its enzymatic activity, is a major etiologic factor for atopic dry skin symptoms via an unknown mechanism.
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Affiliation(s)
- Miho Sashikawa-Kimura
- Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan; (M.S.-K.); (M.R.H.); (H.T.); (M.O.)
| | - Mariko Takada
- Center for Bioscience Research and Education, Utsunomiya University, 350 Mine, Utsunomiya 321-8505, Tochigi, Japan; (M.T.); (X.X.)
| | - Md Razib Hossain
- Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan; (M.S.-K.); (M.R.H.); (H.T.); (M.O.)
| | - Hidetoshi Tsuda
- Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan; (M.S.-K.); (M.R.H.); (H.T.); (M.O.)
| | - Xiaonan Xie
- Center for Bioscience Research and Education, Utsunomiya University, 350 Mine, Utsunomiya 321-8505, Tochigi, Japan; (M.T.); (X.X.)
| | - Mayumi Komine
- Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan; (M.S.-K.); (M.R.H.); (H.T.); (M.O.)
| | - Mamitaro Ohtsuki
- Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan; (M.S.-K.); (M.R.H.); (H.T.); (M.O.)
| | - Genji Imokawa
- Center for Bioscience Research and Education, Utsunomiya University, 350 Mine, Utsunomiya 321-8505, Tochigi, Japan; (M.T.); (X.X.)
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Monedeiro F, Ehall B, Tiffner K, Eberl A, Svehlikova E, Prietl B, Pfeifer V, Senekowitsch J, Remm A, Rebane A, Magnes C, Pieber T, Sinner F, Birngruber T. Characterization of Inflammatory Mediators and Metabolome in Interstitial Fluid Collected with Dermal Open Flow Microperfusion before and at the End of Dupilumab Treatment in Atopic Dermatitis. J Proteome Res 2024; 23:3496-3514. [PMID: 38986055 PMCID: PMC11304394 DOI: 10.1021/acs.jproteome.4c00153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/07/2024] [Accepted: 06/20/2024] [Indexed: 07/12/2024]
Abstract
Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.
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Affiliation(s)
- Fernanda Monedeiro
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Barbara Ehall
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- BioTechMed, Mozartgasse
12, Graz 8010, Austria
| | - Katrin Tiffner
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Anita Eberl
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Eva Svehlikova
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
| | - Barbara Prietl
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- Center
for Biomarker Research in Medicine (CBmed) GmbH, Stiftingtalstrasse 5, Graz 8010, Austria
| | - Verena Pfeifer
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- Center
for Biomarker Research in Medicine (CBmed) GmbH, Stiftingtalstrasse 5, Graz 8010, Austria
| | - Julia Senekowitsch
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
| | - Anu Remm
- Institute
of Biomedicine and Translational Medicine, University of Tartu, Biomeedikum, Ravila 19, Tartu 50411, Estonia
| | - Ana Rebane
- Institute
of Biomedicine and Translational Medicine, University of Tartu, Biomeedikum, Ravila 19, Tartu 50411, Estonia
| | - Christoph Magnes
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Thomas Pieber
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- Center
for Biomarker Research in Medicine (CBmed) GmbH, Stiftingtalstrasse 5, Graz 8010, Austria
| | - Frank Sinner
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
| | - Thomas Birngruber
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
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De Donato DP, Effner R, Nordengrün M, Lechner A, Darisipudi MN, Volz T, Hagl B, Bröker BM, Renner ED. Staphylococcus aureus Serine protease-like protein A (SplA) induces IL-8 by keratinocytes and synergizes with IL-17A. Cytokine 2024; 180:156634. [PMID: 38810500 DOI: 10.1016/j.cyto.2024.156634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 04/15/2024] [Accepted: 04/30/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Serine protease-like (Spl) proteins produced by Staphylococcus (S.) aureus have been associated with allergic inflammation. However, effects of Spls on the epidermal immune response have not been investigated. OBJECTIVES To assess the epidermal immune response to SplA, SplD and SplE dependent on differentiation of keratinocytes and a Th2 or Th17 cytokine milieu. METHODS Human keratinocytes of healthy controls and a STAT3-hyper-IgE syndrome (STAT3-HIES) patient were cultured in different calcium concentrations in the presence of Spls and Th2 or Th17 cytokines. Keratinocyte-specific IL-8 production and concomitant migration of neutrophils were assessed. RESULTS SplE and more significantly SplA, induced IL-8 in keratinocytes. Suprabasal-like keratinocytes showed a higher Spl-mediated IL-8 production and neutrophil migration compared to basal-like keratinocytes. Th17 cytokines amplified Spl-mediated IL-8 production, which correlated with neutrophil recruitment. Neutrophil recruitment by keratinocytes of the STAT3-HIES patient was similar to healthy control cells. CONCLUSION S. aureus-specific Spl proteases synergized with IL-17A on human keratinocytes with respect to IL-8 release and neutrophil migration, highlighting the importance of keratinocytes and Th17 immunity in barrier function.
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Affiliation(s)
- D P De Donato
- Translational Immunology in Environmental Medicine, School of Medicine and Health, Technical University of Munich, Munich, Germany; Vascular Surgery, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - R Effner
- Translational Immunology in Environmental Medicine, School of Medicine and Health, Technical University of Munich, Munich, Germany; Institute of Environmental Medicine, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany; Translational Immunology, Faculty of Medicine, University of Augsburg, Germany
| | - M Nordengrün
- Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
| | - A Lechner
- Translational Immunology in Environmental Medicine, School of Medicine and Health, Technical University of Munich, Munich, Germany; Translational Immunology, Faculty of Medicine, University of Augsburg, Germany
| | - M N Darisipudi
- Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
| | - T Volz
- Department of Dermatology and Allergology, School of Medicine, Technical University of Munich, Munich, Germany
| | - B Hagl
- Translational Immunology in Environmental Medicine, School of Medicine and Health, Technical University of Munich, Munich, Germany; Institute of Environmental Medicine, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany; Translational Immunology, Faculty of Medicine, University of Augsburg, Germany
| | - B M Bröker
- Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
| | - E D Renner
- Translational Immunology in Environmental Medicine, School of Medicine and Health, Technical University of Munich, Munich, Germany; Institute of Environmental Medicine, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany; Translational Immunology, Faculty of Medicine, University of Augsburg, Germany; Department of Pediatrics, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
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6
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Moon S, Stasikowska-Kanicka O, Wągrowska-Danilewicz M, Hawro M, Metz M, Maurer M, Hawro T. Clinically uninvolved but not healthy-The skin of patients with atopic dermatitis is primed for itch and inflammation. J Eur Acad Dermatol Venereol 2024; 38:1089-1100. [PMID: 38063249 DOI: 10.1111/jdv.19694] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/26/2023] [Indexed: 05/26/2024]
Abstract
BACKGROUND Atopic dermatitis (AD) is a highly prevalent inflammatory skin disorder characterized by episodic exacerbations and remissions. Why the clinically healthy skin of AD patients becomes rapidly inflamed and very pruritic is poorly understood. OBJECTIVE To investigate cowhage- and histamine-induced itch and skin expression levels of their target receptors in lesional and non-lesional skin of AD, compared to the skin of patients with psoriasis, chronic spontaneous urticaria (CSU) and healthy subjects. METHODS Patients with AD, psoriasis and chronic spontaneous urticaria (CSU) as well as healthy control subjects (HC) (n = 20 each) were assessed for differences in itch parameters, neurogenic flare reaction and local blood flow responses to skin provocations with cowhage and histamine. Skin biopsies from 10 AD, 10 psoriasis,11 CSU and 12 HC were obtained to assess expression of protease-activated receptors 2 and 4 (PAR-2, PAR-4), histamine H1 and H4 receptors (H1R, H4R), and mast cells. RESULTS Provocation of non-lesional skin of AD patients with cowhage resulted in prolonged itch (p = 0.020), which was not observed in psoriasis and CSU. Significantly prolonged and more intense cowhage- and histamine-induced itch (for duration, peak and overall intensity) was also observed in lesional AD skin. Diminished neurogenic flare reaction and blood flow after histamine provocation were shown in AD and psoriasis patients. Non-lesional AD skin along with lesional AD and psoriasis skin showed an increased expression of PAR-2 and PAR-4, H1R and H4R. Mast cell number was higher in lesional AD and psoriasis skin (p = 0.006 and p = 0.006, respectively). CONCLUSION The non-lesional skin of AD patients markedly differs from healthy skin in cowhage-induced itch responses and the expression of receptors for proteases and histamine. Proactive therapeutic interventions that downregulate these receptors may prevent episodic exacerbation in AD.
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Affiliation(s)
- S Moon
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - O Stasikowska-Kanicka
- Department of Diagnostic Techniques in Pathomorphology, Medical University of Lodz, Lodz, Poland
| | - M Wągrowska-Danilewicz
- Department of Diagnostic Techniques in Pathomorphology, Medical University of Lodz, Lodz, Poland
| | - M Hawro
- Department of Dermatology, Allergology and Venerology, Institute and Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - M Metz
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - M Maurer
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - T Hawro
- Department of Dermatology, Allergology and Venerology, Institute and Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
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Schmuth M, Eckmann S, Moosbrugger-Martinz V, Ortner-Tobider D, Blunder S, Trafoier T, Gruber R, Elias PM. Skin Barrier in Atopic Dermatitis. J Invest Dermatol 2024; 144:989-1000.e1. [PMID: 38643989 DOI: 10.1016/j.jid.2024.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 04/23/2024]
Abstract
A compromised permeability barrier is a hallmark of atopic dermatitis (AD). Localized to the outermost skin layer, the stratum corneum (SC) is critically dependent on terminal differentiation of epidermal keratinocytes, which transform into protein-rich corneocytes surrounded by extracellular lamellae of unique epidermal lipids, conferring permeability barrier function. These structures are disrupted in AD. A leaky barrier is prone to environmental insult, which in AD elicits type 2-dominant inflammation, in turn resulting in a vicious cycle further impairing the SC structure. Therapies directed at enforcing SC structure and anti-inflammatory strategies administered by topical and systemic route as well as UV therapy have differential effects on the permeability barrier. The expanding armamentarium of therapeutic modalities for AD treatment warrants optimization of their effects on permeability barrier function.
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Affiliation(s)
- Matthias Schmuth
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria; Institute for Pediatric Dermatology and Rare Diseases, Karl Landsteiner Society, Innsbruck, Austria.
| | - Sonja Eckmann
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | | | | | - Stefan Blunder
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | - Thomas Trafoier
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | - Robert Gruber
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria; Institute for Pediatric Dermatology and Rare Diseases, Karl Landsteiner Society, Innsbruck, Austria
| | - Peter M Elias
- Dermatology, Veteran Affairs Health Care System, San Francisco, California, USA; University of California San Francisco, San Francisco, California, USA
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8
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Jiao Q, Zhi L, You B, Wang G, Wu N, Jia Y. Skin homeostasis: Mechanism and influencing factors. J Cosmet Dermatol 2024; 23:1518-1526. [PMID: 38409936 DOI: 10.1111/jocd.16155] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 12/08/2023] [Accepted: 12/17/2023] [Indexed: 02/28/2024]
Abstract
BACKGROUND The skin is the largest organ in the human body, not only resisting the invasion of harmful substances, but also preventing the loss of moisture and nutrients. Maintaining skin homeostasis is a prerequisite for the proper functioning of the body. Any damage to the skin can lead to a decrease in local homeostasis, such as ultraviolet radiation, seasonal changes, and air pollution, which can damage the skin tissue and affect the function of the skin barrier. OBJECTIVE This article reviews the maintenance mechanism and influencing factors of skin homeostasis and the symptoms of homeostasis imbalance. METHODS We searched for articles published between 1990 and 2022 in English and Chinese using PubMed, Web of Science, CNKI, and other databases in the subject area of dermatology, using the following search terms in various combinations: "skin homeostasis," "skin barrier," and "unstable skin." Based on our results, we further refined our search criteria to include a series of common skin problems caused by the destruction of skin homeostasis and its treatments. Limitations include the lack of research on dermatological and cosmetic problems triggered by the disruption of skin homeostasis. RESULTS This study describes the neuroendocrine-immune system, skin barrier structure, and skin metabolic system that maintain skin homeostasis. In addition, we discuss several common symptoms that occur when skin homeostasis is out of balance, such as dryness, redness, acne, sensitivity, and aging, and explain the mechanism of these symptoms. CONCLUSION This article provides an update and review for students and practitioners, and provides a theoretical basis for the development of skin care products for the maintenance and repair of skin homeostasis.
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Affiliation(s)
- Qian Jiao
- Key Laboratory of Cosmetic of China National Light Industry, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
| | - Leilei Zhi
- R&D Center, PeiLai Group Co., Ltd, Shanghai, China
| | - Bing You
- R&D Center, PeiLai Group Co., Ltd, Shanghai, China
| | | | - Nan Wu
- R&D Center, PeiLai Group Co., Ltd, Shanghai, China
| | - Yan Jia
- Key Laboratory of Cosmetic of China National Light Industry, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
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9
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Kawakita K, Kouzaki H, Murao T, Kubo Y, Nishiguchi T, Nakamura K, Arai H, Matsumoto K, Tojima I, Shimizu S, Shimizu T. Role of basal cells in nasal polyp epithelium in the pathophysiology of eosinophilic chronic rhinosinusitis (eCRS). Allergol Int 2024:S1323-8930(24)00045-5. [PMID: 38670810 DOI: 10.1016/j.alit.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/10/2024] [Accepted: 03/07/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Basal cell hyperplasia is commonly observed in nasal polyp epithelium of eosinophilic chronic rhinosinusitis (eCRS). We examined the function and mechanisms of basal cell hyperplasia in the pathophysiology of eCRS. METHODS We found that normal human bronchial epithelial (NHBE) cells obtained basal cell characteristics when cultured with PneumaCult™-Ex Plus Medium. Most of the cells passaged three times expressed basal cell surface markers CD49f and CD271 by flow cytometry, and basal cell nuclear marker p63 by immunohistochemical staining. We named these NHBE cells with basal cell characteristics cultured Basal-like cells (cBC), and NHBE cells cultured with BEGM™ cultured Epithelial cells (cEC). The characteristics of cBC and cEC were examined and compared by RNA sequencing, RT-PCR, ELISA, and cell proliferation studies. RESULTS RNA sequencing revealed that cBC showed higher gene expression of thymic stromal lymphopoietin (TSLP), IL-8, TLR3, and TLR4, and lower expression of PAR-2 compared with cEC. The mRNA expression of TSLP, IL-8, TLR3, and TLR4 was significantly increased in cBC, and that of PAR-2 was significantly increased in cEC by RT-PCR. Poly(I:C)-induced TSLP production and LPS-induced IL-8 production were significantly increased in cBC. IL-4 and IL-13 stimulated the proliferation of cBC. Finally, the frequency of p63-positive basal cells was increased in nasal polyp epithelium of eCRS, and Ki67-positive proliferating cells were increased in p63-positive basal cells. CONCLUSIONS Type 2 cytokines IL-4 and IL-13 induce basal cell hyperplasia, and basal cells exacerbate type 2 inflammation by producing TSLP in nasal polyp of eCRS.
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Affiliation(s)
- Kento Kawakita
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Hideaki Kouzaki
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan.
| | - Takuya Murao
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Yoshihito Kubo
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Tatsuji Nishiguchi
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Keigo Nakamura
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Hiroyuki Arai
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Koji Matsumoto
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Ichiro Tojima
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Shino Shimizu
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Takeshi Shimizu
- Department of Otorhinolaryngology-Head and Neck Surgery, Shiga University of Medical Science, Otsu, Japan
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10
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Chittock J, Kay L, Brown K, Cooke A, Lavender T, Cork MJ, Danby SG. Association between skin barrier development and early-onset atopic dermatitis: A longitudinal birth cohort study. J Allergy Clin Immunol 2024; 153:732-741.e8. [PMID: 37926123 DOI: 10.1016/j.jaci.2023.10.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 10/16/2023] [Accepted: 10/25/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND A diagnosis of atopic dermatitis (AD) is common during infancy; however, it is unclear whether differential skin barrier development defines this period and signals disease onset in predisposed individuals. OBJECTIVE We sought to study (NCT03143504) and assess the feasibility of remote skin testing from birth to monitor skin barrier maturation and model association with an AD diagnosis by age 12 months. METHODS Biophysical testing and infrared spectroscopy were conducted at the maternity ward and family home. Tape stripping collected samples for desquamatory protease and natural moisturizing factor analysis. The 4 common European filaggrin risk alleles were screened. RESULTS A total of 128 infants completed the study, with 20% developing mild disease. Significant changes in permeability barrier function, desquamatory protease activity, and molecular composition assessed spectroscopically were observed longitudinally, but only subtle evidence of differential skin barrier development was noted between infant subgroups. Common filaggrin risk alleles were strongly associated with early-onset disease and conferred a significant reduction in natural moisturizing factor and water content by age 4 weeks. Accounting for a family history of atopy, these parameters alongside a greater lipid/protein ratio and reduced chymotrypsin-like activity at birth were associated with AD. Measured in ambient conditions, transepidermal water loss did not signal disease risk at any stage. CONCLUSIONS Skin barrier dysfunction lacked an acquired modality but was considered proportional to cohort severity and suggests that a portfolio of tests used in a community setting has the potential to improve current AD risk evaluations from birth.
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Affiliation(s)
- John Chittock
- Sheffield Dermatology Research, Division of Clinical Medicine, University of Sheffield Medical School, Sheffield, United Kingdom.
| | - Linda Kay
- Sheffield Dermatology Research, Division of Clinical Medicine, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Kirsty Brown
- Sheffield Dermatology Research, Division of Clinical Medicine, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Alison Cooke
- Centre for NMAHP Research and Education Excellence, University Hospitals of North Midlands NHS Trust, Royal Stoke University Hospital and School of Nursing and Midwifery, Keele University, Keele, United Kingdom
| | - Tina Lavender
- Centre for Childbirth, Women's and Newborn Health, Department of International Public Health, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
| | - Michael J Cork
- Sheffield Dermatology Research, Division of Clinical Medicine, University of Sheffield Medical School, Sheffield, United Kingdom; Paediatric Dermatology Clinic, Sheffield Children's Hospital, Sheffield, United Kingdom
| | - Simon G Danby
- Sheffield Dermatology Research, Division of Clinical Medicine, University of Sheffield Medical School, Sheffield, United Kingdom
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11
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Haferland I, Pinter A, Rossmanith T, Diehl S, Buerger C, Ickelsheimer T, Kaufmann R, Koenig A. A Novel Epidermis Model Using Primary Hidradenitis Suppurativa Keratinocytes. J Tissue Eng Regen Med 2024; 2024:4363876. [PMID: 40225748 PMCID: PMC11918907 DOI: 10.1155/2024/4363876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 01/02/2024] [Accepted: 02/12/2024] [Indexed: 04/15/2025]
Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease. Patients can present with inflammatory nodules, abscesses up to fistulas, or sinus tracts in intertriginous body parts. Occlusion of the sebaceous gland unit leads to its rupture, with a subsequent exuberant immune response. Given there is still no causative therapy, to better understand HS and develop novel therapeutic concepts, research activities in the HS field are constantly growing. Primary skin cells, blood cells, and ex vivo explant cultures from HS patients have been previously used as HS cell culture models. In vitro reconstituted epidermal models are established to study inflammatory dermatoses, such as psoriasis or atopic dermatitis. For HS, the exploration of epidermis models would be an excellent addition, e.g., biomarkers or barrier function in testing new topic treatment options. We therefore established a stratified in vitro HS epidermis model based on primary cells from HS lesions. After isolating keratinocytes from lesional skin, we cultured them submerged in a transwell system. To induce differentiation, we then lifted them to the air-liquid interface. Immunohistochemical staining demonstrated that our HS-epidermis model meets the expected differentiation pattern. In addition, we detected the secretion of the inflammatory cytokines interleukin-1β and TNF-α.
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Affiliation(s)
- Isabel Haferland
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Andreas Pinter
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Tanja Rossmanith
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, Frankfurt am Main 60596, Germany
| | - Sandra Diehl
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Claudia Buerger
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Tanja Ickelsheimer
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Roland Kaufmann
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Anke Koenig
- Goethe University Frankfurt, University Hospital, Department of Dermatology, Venereology and Allergology, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
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12
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Şahin Bektay H, Sağıroğlu AA, Bozali K, Güler EM, Güngör S. The Design and Optimization of Ceramide NP-Loaded Liposomes to Restore the Skin Barrier. Pharmaceutics 2023; 15:2685. [PMID: 38140026 PMCID: PMC10747297 DOI: 10.3390/pharmaceutics15122685] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/08/2023] [Accepted: 10/25/2023] [Indexed: 12/24/2023] Open
Abstract
The impairment of skin integrity derived from derangement of the orthorhombic lateral organization is mainly caused by dysregulation of ceramide amounts in the skin barrier. Ceramides, fatty acids, and cholesterol-containing nano-based formulations have been used to impair the skin barrier. However, there is still a challenge to formulate novel formulations consisting of ceramides due to their chemical structure, poor aqueous solubility, and high molecular weight. In this study, the design and optimization of Ceramide 3 (CER-NP)-loaded liposomes are implemented based on response surface methodology (RSM). The optimum CER-NP-loaded liposome was selected based on its particle size (PS) and polydispersity index (PDI). The optimum CER-NP-loaded liposome was imagined by observing the encapsulation by using a confocal laser scanning microscope (CLSM) within fluorescently labeled CER-NP. The characteristic liquid crystalline phase and lipid chain conformation of CER-NP-loaded liposomes were determined using attenuated total reflectance infrared spectroscopy (ATR-IR). The CER-NP-loaded liposomes were imagined using a field emission scanning electron microscope (FE-SEM). Finally, the in vitro release of CER-NP from liposomes was examined using modified Franz Cells. The experimental and predicted results were well correlated. The CLSM images of optimized liposomes were conformable with the other studies, and the encapsulation efficiency of CER-NP was 93.84 ± 0.87%. ATR-IR analysis supported the characteristics of the CER-NP-loaded liposome. In addition, the lipid chain conformation shows similarity with skin barrier lipid organization. The release pattern of CER-NP liposomes was fitted with the Korsmeyer-Peppas model. The cytotoxicity studies carried out on HaCaT keratinocytes supported the idea that the liposomes for topical administration of CER-NP could be considered relatively safe. In conclusion, the optimized CER-NP-loaded liposomes could have the potential to restore the skin barrier function.
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Affiliation(s)
- Hümeyra Şahin Bektay
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Türkiye
- Health Science Institute, Istanbul University, Istanbul 34126, Türkiye
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Bezmialem Vakıf University, Istanbul 34093, Türkiye
| | - Ali Asram Sağıroğlu
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Bezmialem Vakıf University, Istanbul 34093, Türkiye
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University-Cerrahpaşa, Istanbul 34500, Türkiye
| | - Kübra Bozali
- Department of Medical Biochemistry, Faculty of Hamidiye Medicine, University of Health Science, Istanbul 34668, Türkiye
| | - Eray Metin Güler
- Department of Medical Biochemistry, Faculty of Hamidiye Medicine, University of Health Science, Istanbul 34668, Türkiye
| | - Sevgi Güngör
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Türkiye
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13
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Bouwstra JA, Nădăban A, Bras W, McCabe C, Bunge A, Gooris GS. The skin barrier: An extraordinary interface with an exceptional lipid organization. Prog Lipid Res 2023; 92:101252. [PMID: 37666282 PMCID: PMC10841493 DOI: 10.1016/j.plipres.2023.101252] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/06/2023]
Abstract
The barrier function of the skin is primarily located in the stratum corneum (SC), the outermost layer of the skin. The SC is composed of dead cells with highly organized lipid lamellae in the intercellular space. As the lipid matrix forms the only continuous pathway, the lipids play an important role in the permeation of compounds through the SC. The main lipid classes are ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). Analysis of the SC lipid matrix is of crucial importance in understanding the skin barrier function, not only in healthy skin, but also in inflammatory skin diseases with an impaired skin barrier. In this review we provide i) a historical overview of the steps undertaken to obtain information on the lipid composition and organization in SC of healthy skin and inflammatory skin diseases, ii) information on the role CERs, CHOL and FFAs play in the lipid phase behavior of very complex lipid model systems and how this knowledge can be used to understand the deviation in lipid phase behavior in inflammatory skin diseases, iii) knowledge on the role of both, CER subclasses and chain length distribution, on lipid organization and lipid membrane permeability in complex and simple model systems with synthetic CERs, CHOL and FFAs, iv) similarity in lipid phase behavior in SC of different species and complex model systems, and vi) future directions in modulating lipid composition that is expected to improve the skin barrier in inflammatory skin diseases.
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Affiliation(s)
- Joke A Bouwstra
- Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
| | - Andreea Nădăban
- Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Wim Bras
- Chemical Sciences Division, Oak Ridge National Laboratory, One Bethel Valley Road, Oak Ridge, TN 37831, United States of America
| | - Clare McCabe
- School of Engineering & Physical Science, Heriot-Watt University, Edinburgh, Scotland, UK
| | - Annette Bunge
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO 80401, United States of America
| | - Gerrit S Gooris
- Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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14
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Sutter CH, Azim S, Wang A, Bhuju J, Simpson AS, Uberoi A, Grice EA, Sutter TR. Ligand Activation of the Aryl Hydrocarbon Receptor Upregulates Epidermal Uridine Diphosphate Glucose Ceramide Glucosyltransferase and Glucosylceramides. J Invest Dermatol 2023; 143:1964-1972.e4. [PMID: 37004877 PMCID: PMC10529782 DOI: 10.1016/j.jid.2023.03.1662] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/08/2023] [Accepted: 03/14/2023] [Indexed: 04/03/2023]
Abstract
Ligand activation of the aryl hydrocarbon receptor (AHR) accelerates keratinocyte differentiation and the formation of the epidermal permeability barrier. Several classes of lipids, including ceramides, are critical to the epidermal permeability barrier. In normal human epidermal keratinocytes, the AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased RNA levels of ceramide metabolism and transport genes: uridine diphosphate glucose ceramide glucosyltransferase (UGCG), ABCA12, GBA1, and SMPD1. Levels of abundant skin ceramides were also increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin. These included the metabolites synthesized by UGCG, glucosylceramides, and acyl glucosylceramides. Chromatin immunoprecipitation-sequence analysis and luciferase reporter assays identified UGCG as a direct AHR target. The AHR antagonist, GNF351, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated RNA and transcriptional increases. Tapinarof, an AHR ligand approved for the treatment of psoriasis, increased UGCG RNA, protein, and its lipid metabolites hexosylceramides as well as increased the RNA expression of ABCA12, GBA1, and SMPD1. In Ahr-null mice, Ugcg RNA and hexosylceramides were lower than those in the wild type. These results indicate that the AHR regulates the expression of UGCG, a ceramide-metabolizing enzyme required for ceramide trafficking, keratinocyte differentiation, and epidermal permeability barrier formation.
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Affiliation(s)
- Carrie Hayes Sutter
- Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA
| | - Shafquat Azim
- Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Anyou Wang
- Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA
| | - Jyoti Bhuju
- Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA; Sanegene Bio USA, Cambridge, Massachusetts, USA
| | - Amelia S Simpson
- Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA
| | - Aayushi Uberoi
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Elizabeth A Grice
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Thomas R Sutter
- Department of Biological Sciences, The University of Memphis, Memphis, Tennessee, USA; Department of Chemistry, The University of Memphis, Memphis, Tennessee, USA.
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15
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Machado M, Silva S, Costa EM. Are Antimicrobial Peptides a 21st-Century Solution for Atopic Dermatitis? Int J Mol Sci 2023; 24:13460. [PMID: 37686269 PMCID: PMC10488019 DOI: 10.3390/ijms241713460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/27/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is the result of various environmental, bacterial and genetic stimuli, which culminate in the disruption of the skin's barrier function. Characterized by highly pruritic skin lesions, xerosis and an array of comorbidities among which skin infections are the most common, this condition results in both a significant loss of quality of life and in the need for life-long treatments (e.g., corticosteroids, monoclonal antibodies and regular antibiotic intake), all of which may have harmful secondary effects. This, in conjunction with AD's rising prevalence, made the development of alternative treatment strategies the focus of both the scientific community and the pharmaceutical industry. Given their potential to both manage the skin microbiome, fight infections and even modulate the local immune response, the use of antimicrobial peptides (AMPs) from more diverse origins has become one of the most promising alternative solutions for AD management, with some being already used with some success towards this end. However, their production and use also exhibit some limitations. The current work seeks to compile the available information and provide a better understanding of the state of the art in the understanding of AMPs' true potential in addressing AD.
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Affiliation(s)
| | - Sara Silva
- CBQF Centro de Biotecnologia e Química Fina Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Rua Diogo Botelho 1327, 4169-005 Porto, Portugal;
| | - Eduardo M. Costa
- CBQF Centro de Biotecnologia e Química Fina Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Rua Diogo Botelho 1327, 4169-005 Porto, Portugal;
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16
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Çetinarslan T, Kümper L, Fölster-Holst R. The immunological and structural epidermal barrier dysfunction and skin microbiome in atopic dermatitis-an update. Front Mol Biosci 2023; 10:1159404. [PMID: 37654796 PMCID: PMC10467310 DOI: 10.3389/fmolb.2023.1159404] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 08/04/2023] [Indexed: 09/02/2023] Open
Abstract
Atopic dermatitis (AD) is a common, chronic and relapsing inflammatory skin disease with various clinical presentations and combinations of symptoms. The pathophysiology of AD is complex and multifactorial. There are several factors involved in the etiopathogenesis of AD including structural and immunological epidermal barrier defect, imbalance of the skin microbiome, genetic background and environmental factors. Alterations in structural proteins, lipids, proteases, and their inhibitors, lead to the impairment of the stratum corneum which is associated with the increased skin penetration and transepidermal water loss. The elevated serum immunoglobulin E levels and blood eosinophilia have been shown in the majority of AD patients. Type 2 T-helper cell immune pathway with increased expression of interleukin (IL)-4, IL-5, and IL-13, has an important role in the etiopathogenesis of AD. Both T cells and keratinocytes contribute to epidermal barrier impairment in AD via a dynamic interaction of cytokines and chemokines. The skin microbiome is another factor of relevance in the etiopathogenesis of AD. It has been shown that during AD flares, Staphylococcus aureus (S. aureus) colonization increased, while Staphylococcus epidermidis (S. epidermidis) decreased. On the contrary, S. epidermidis and species of Streptococcus, Corynebacterium and Propionibacterium increased during the remision phases. However, it is not clear whether skin dysbiosis is one of the symptoms or one of the causes of AD. There are several therapeutic options, targeting these pathways which play a critical role in the etiopathogenesis of AD. Although topical steroids are the mainstay of the treatment of AD, new biological therapies including IL-4, IL-13, and IL-31 inhibitors, as well as Janus kinase inhibitors (JAKi), increasingly gain more importance with new advances in the therapy of AD. In this review, we summarize the role of immunological and structural epidermal barrier dysfunction, immune abnormalities, impairment of lipids, filaggrin mutation and skin microbiome in the etiopathogenesis of AD, as well as the therapeutic options for AD and their effects on these abnormalities in AD skin.
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Affiliation(s)
- Tubanur Çetinarslan
- Department of Dermatology and Venereology, Manisa Celal Bayar University, Manisa, Türkiye
| | - Lisa Kümper
- MEDICE Arzneimittel Pütter GmbH and Co. KG, Iserlohn, Germany
| | - Regina Fölster-Holst
- Department of Dermatology-Venereology and Allergology, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
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17
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De La Cruz NC, Möckel M, Niehues H, Rübsam M, Malter W, Zinser M, Krummenacher C, Knebel-Mörsdorf D. Ex Vivo Infection of Human Skin Models with Herpes Simplex Virus 1: Accessibility of the Receptor Nectin-1 during Formation or Impairment of Epidermal Barriers Is Restricted by Tight Junctions. J Virol 2023; 97:e0026223. [PMID: 37289055 PMCID: PMC10308952 DOI: 10.1128/jvi.00262-23] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/18/2023] [Indexed: 06/09/2023] Open
Abstract
Herpes simplex virus 1 (HSV-1) must overcome epidermal barriers to reach its receptors on keratinocytes and initiate infection in human skin. The cell-adhesion molecule nectin-1, which is expressed in human epidermis, acts as an efficient receptor for HSV-1 but is not within reach of the virus upon exposure of human skin under nonpathological conditions. Atopic dermatitis skin, however, can provide an entry portal for HSV-1 emphasizing the role of impaired barrier functions. Here, we explored how epidermal barriers impact HSV-1 invasion in human epidermis and influence the accessibility of nectin-1 for the virus. Using human epidermal equivalents, we observed a correlation of the number of infected cells with tight-junction formation, suggesting that mature tight junctions prior to formation of the stratum corneum prevent viral access to nectin-1. Consequently, impaired epidermal barriers driven by Th2-inflammatory cytokines interleukin 4 (IL-4) and IL-13 as well as the genetic predisposition of nonlesional atopic dermatitis keratinocytes correlated with enhanced infection supporting the impact of functional tight junctions for preventing infection in human epidermis. Comparable to E-cadherin, nectin-1 was distributed throughout the epidermal layers and localized just underneath the tight-junctions. While nectin-1 was evenly distributed on primary human keratinocytes in culture, the receptor was enriched at lateral surfaces of basal and suprabasal cells during differentiation. Nectin-1 showed no major redistribution in the thickened atopic dermatitis and IL-4/IL-13-treated human epidermis in which HSV-1 can invade. However, nectin-1 localization toward tight junction components changed, suggesting that defective tight-junction barriers make nectin-1 accessible for HSV-1 which enables facilitated viral penetration. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a widely distributed human pathogen which productively infects epithelia. The open question is which barriers of the highly protected epithelia must the virus overcome to reach its receptor nectin-1. Here, we used human epidermal equivalents to understand how physical barrier formation and nectin-1 distribution contribute to successful viral invasion. Inflammation-induced barrier defects led to facilitated viral penetration strengthening the role of functional tight-junctions in hindering viral access to nectin-1 that is localized just underneath tight junctions and distributed throughout all layers. We also found nectin-1 ubiquitously localized in the epidermis of atopic dermatitis and IL-4/IL-13-treated human skin implying that impaired tight-junctions in combination with a defective cornified layer allow the accessibility of nectin-1 to HSV-1. Our results support that successful invasion of HSV-1 in human skin relies on defective epidermal barriers, which not only include a dysfunctional cornified layer but also depend on impaired tight junctions.
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Affiliation(s)
- Nydia C. De La Cruz
- Center for Biochemistry, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Maureen Möckel
- Center for Biochemistry, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hanna Niehues
- Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Matthias Rübsam
- Department Cell Biology of the Skin, University Hospital Cologne, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-associated Diseases, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Wolfram Malter
- Department of Gynecology and Obstetrics, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Max Zinser
- Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Claude Krummenacher
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, New Jersey, USA
| | - Dagmar Knebel-Mörsdorf
- Center for Biochemistry, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of Pediatrics, University Hospital Cologne, University of Cologne, Cologne, Germany
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18
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Hua X, Blosch CD, Dorsey H, Ficaro MK, Wallace NL, Hsung RP, Dai J. Epidermal Loss of RORα Enhances Skin Inflammation in a MC903-Induced Mouse Model of Atopic Dermatitis. Int J Mol Sci 2023; 24:10241. [PMID: 37373387 DOI: 10.3390/ijms241210241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease featuring skin barrier dysfunction and immune dysregulation. Previously, we reported that the retinoid-related orphan nuclear receptor RORα was highly expressed in the epidermis of normal skin. We also found that it positively regulated the expression of differentiation markers and skin barrier-related genes in human keratinocytes. In contrast, epidermal RORα expression was downregulated in the skin lesions of several inflammatory skin diseases, including AD. In this study, we generated mouse strains with epidermis-specific Rora ablation to understand the roles of epidermal RORα in regulating AD pathogenesis. Although Rora deficiency did not cause overt macroscopic skin abnormalities at the steady state, it greatly amplified MC903-elicited AD-like symptoms by intensifying skin scaliness, increasing epidermal hyperproliferation and barrier impairment, and elevating dermal immune infiltrates, proinflammatory cytokines, and chemokines. Despite the normal appearance at the steady state, Rora-deficient skin showed microscopic abnormalities, including mild epidermal hyperplasia, increased TEWL, and elevated mRNA expression of Krt16, Sprr2a, and Tslp genes, indicating subclinical impairment of epidermal barrier functions. Our results substantiate the importance of epidermal RORα in partially suppressing AD development by maintaining normal keratinocyte differentiation and skin barrier function.
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Affiliation(s)
- Xiangmei Hua
- School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
| | - Conrad Dean Blosch
- Biomedical Research Model Services, University of Wisconsin, Madison, WI 53705, USA
| | - Hannah Dorsey
- School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
| | - Maria K Ficaro
- School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
| | - Nicole L Wallace
- School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
| | - Richard P Hsung
- School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
| | - Jun Dai
- School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA
- UW Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA
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19
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Pfrieger FW. The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism. Prog Lipid Res 2023; 90:101225. [PMID: 37003582 DOI: 10.1016/j.plipres.2023.101225] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/27/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
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20
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Kleuser B, Bäumer W. Sphingosine 1-Phosphate as Essential Signaling Molecule in Inflammatory Skin Diseases. Int J Mol Sci 2023; 24:ijms24021456. [PMID: 36674974 PMCID: PMC9863039 DOI: 10.3390/ijms24021456] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/04/2023] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
Sphingolipids are crucial molecules of the mammalian epidermis. The formation of skin-specific ceramides contributes to the formation of lipid lamellae, which are important for the protection of the epidermis from excessive water loss and protect the skin from the invasion of pathogens and the penetration of xenobiotics. In addition to being structural constituents of the epidermal layer, sphingolipids are also key signaling molecules that participate in the regulation of epidermal cells and the immune cells of the skin. While the importance of ceramides with regard to the proliferation and differentiation of skin cells has been known for a long time, it has emerged in recent years that the sphingolipid sphingosine 1-phosphate (S1P) is also involved in processes such as the proliferation and differentiation of keratinocytes. In addition, the immunomodulatory role of this sphingolipid species is becoming increasingly apparent. This is significant as S1P mediates a variety of its actions via G-protein coupled receptors. It is, therefore, not surprising that dysregulation in the signaling pathways of S1P is involved in the pathophysiological conditions of skin diseases. In the present review, the importance of S1P in skin cells, as well as the immune cells of the skin, is elaborated. In particular, the role of the molecule in inflammatory skin diseases will be discussed. This is important because interfering with S1P signaling pathways may represent an innovative option for the treatment of inflammatory skin diseases.
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Affiliation(s)
- Burkhard Kleuser
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise Str. 2+4, 14195 Berlin, Germany
- Correspondence: (B.K.); (W.B.)
| | - Wolfgang Bäumer
- Department of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, Koserstr. 20, 14195 Berlin, Germany
- Correspondence: (B.K.); (W.B.)
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21
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Ilves L, Ottas A, Kaldvee B, Abram K, Soomets U, Zilmer M, Jaks V, Kingo K. Metabolomic Differences between the Skin and Blood Sera of Atopic Dermatitis and Psoriasis. Int J Mol Sci 2022; 23:13001. [PMID: 36361789 PMCID: PMC9658722 DOI: 10.3390/ijms232113001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 10/25/2022] [Indexed: 11/12/2023] Open
Abstract
Atopic dermatitis (AD) and psoriasis (PS) are common chronic inflammatory dermatoses. Although the differences at the intercellular and intracellular signaling level between AD and PS are well described, the resulting differences at the metabolism level have not yet been systematically analyzed. We compared the metabolomic profiles of the lesional skin, non-lesional skin and blood sera of AD and PS. Skin biopsies from 15 patients with AD, 20 patients with PS and 17 controls were collected, and 25 patients with AD, 55 patients with PS and 63 controls were recruited for the blood serum analysis. Serum and skin samples were analyzed using a targeted approach to find the concentrations of 188 metabolites and their ratios. A total of 19 metabolites differed in the comparison of lesional skins, one metabolite in non-lesional skins and 5 metabolites in blood sera. Although we found several metabolomic similarities between PS and AD, clear differences were outlined. Sphingomyelins were elevated in lesional skin of AD, implying a deficient barrier function. Increased levels of phosphatidylcholines, carnitines and asymmetric dimethylarginine in PS lesional skin and carnitines amino acids in the PS serum pointed to elevated cell proliferation. The comparison of the metabolomic profiles of AD and PS skin and sera outlined distinct patterns that were well correlated with the differences in the pathogenetic mechanisms of these two chronic inflammatory dermatoses.
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Affiliation(s)
- Liis Ilves
- Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia
- Dermatology Clinic, Tartu University Hospital, 50417 Tartu, Estonia
| | - Aigar Ottas
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
- Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Bret Kaldvee
- Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia
| | - Kristi Abram
- Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia
- Dermatology Clinic, Tartu University Hospital, 50417 Tartu, Estonia
| | - Ursel Soomets
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
- Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Mihkel Zilmer
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
- Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Viljar Jaks
- Dermatology Clinic, Tartu University Hospital, 50417 Tartu, Estonia
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia
| | - Külli Kingo
- Department of Dermatology and Venereology, University of Tartu, 50417 Tartu, Estonia
- Dermatology Clinic, Tartu University Hospital, 50417 Tartu, Estonia
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22
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Leman G, Pavel P, Hermann M, Crumrine D, Elias PM, Minzaghi D, Goudounèche D, Roshardt Prieto NM, Cavinato M, Wanner A, Blunder S, Gruber R, Jansen-Dürr P, Dubrac S. Mitochondrial Activity Is Upregulated in Nonlesional Atopic Dermatitis and Amenable to Therapeutic Intervention. J Invest Dermatol 2022; 142:2623-2634.e12. [PMID: 35341734 DOI: 10.1016/j.jid.2022.01.035] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 01/20/2022] [Accepted: 01/30/2022] [Indexed: 12/12/2022]
Abstract
Previous work has shown increased expression of genes related to oxidative stress in nonlesional atopic dermatitis (ADNL) skin. Although mitochondria are key regulators of ROS production, their function in AD has never been investigated. Energy metabolism and the oxidative stress response were studied in keratinocytes (KCs) from patients with ADNL or healthy controls. Moreover, ADNL human epidermal equivalents were treated with tigecycline or MitoQ. We found that pyruvate and glucose were used as energy substrates by ADNL KCs. Increased mitochondrial oxidation of (very) long-chain fatty acids, associated with enhanced complexes I and II activities, was observed in ADNL KCs. Metabolomic analysis revealed increased tricarboxylic acid cycle turnover. Increased aerobic metabolism generated oxidative stress in ADNL KCs. ADNL human epidermal equivalents displayed increased mitochondrial function and an enhanced oxidative stress response compared with controls. Treatment of ADNL human epidermal equivalents with tigecycline or MitoQ largely corrected the AD profile, including high p-65 NF-κB, abnormal lamellar bodies, and cellular damage. Furthermore, we found that glycolysis supports but does not supersede mitochondrial metabolism in ADNL KCs. Thus, aerobic metabolism predominates in ADNL but leads to oxidative stress. Therefore, mitochondria could be a reservoir of potential therapeutic targets in atopic dermatitis.
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Affiliation(s)
- Geraldine Leman
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Petra Pavel
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin Hermann
- Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Debra Crumrine
- Department of Dermatology, University of California San Francisco, San Francisco, California
| | - Peter M Elias
- Department of Dermatology, University of California San Francisco, San Francisco, California
| | - Deborah Minzaghi
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Dominique Goudounèche
- Center of Electron Microscopy Applied to Biology, Faculty of Medicine Rangueil, Toulouse III, Paul Sabatier University, Toulouse, France
| | - Natalia M Roshardt Prieto
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Maria Cavinato
- Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Andrea Wanner
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Blunder
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Robert Gruber
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Pidder Jansen-Dürr
- Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Austria
| | - Sandrine Dubrac
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
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23
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Goto K, Hiramoto K, Maruyama K, Ooi K. Relationships of pain-causing substances with dry skin and effects of zaltoprofen on alleviation of symptoms in arthritis model mice. Cutan Ocul Toxicol 2022; 41:296-303. [PMID: 36170456 DOI: 10.1080/15569527.2022.2127749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Skin dryness is a symptom of rheumatoid arthritis (RA). However, the mechanisms through which dry skin is induced in RA are unclear. Accordingly, in this study, we characterized substances related to pruritus and pain and then evaluated whether oral administration of zaltoprofen (ZLT) alleviated the symptom of dry skin induced by RA in model mice. DBA/1JJmsSlc collagen-induced arthritis model mice were treated with ZLT, and transepidermal water loss (TEWL), capacitance, and inflammation-, pruritus-, and pain-related markers were assessed. Our findings demonstrated that arthritis model mice treated with ZLT exhibited suppression of increases in TEWL and decreases in capacitance. Furthermore, ZLT also blocked the increase in mast cell numbers, substance P expression, and cyclo-oxygenase-2 expression in the skin and prevented enhancement of plasma levels of thymic stromal lymphopoietin, tumor necrosis factor-α, interleukin-6, histamine, and bradykinin. No changes in plasma levels of corticosterone or reactive oxygen species or skin levels of glucocorticoid receptor were observed in ZLT-treated arthritis model mice. Overall, these findings suggested that patients with RA may benefit from biopharmacy to alleviate joint symptoms and nonsteroidal anti-inflammatory drugs for pain relief and alleviation of skin symptoms.
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Affiliation(s)
- Kenji Goto
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan.,Research Laboratories, Nichinichi Pharmaceutical Co., Ltd., Iga, Japan
| | - Keiichi Hiramoto
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Kiyoko Maruyama
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Kazuya Ooi
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
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24
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Beddoes CM, Gooris GS, Barlow DJ, Lawrence MJ, Dalgliesh RM, Malfois M, Demé B, Bouwstra JA. The importance of ceramide headgroup for lipid localisation in skin lipid models. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2022; 1864:183886. [PMID: 35143742 DOI: 10.1016/j.bbamem.2022.183886] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 06/14/2023]
Abstract
The stratum corneum's lipid matrix is a critical for the skin's barrier function and is primarily composed of ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). The lipids form a long periodicity phase (LPP), a unique trilayer unit cell structure. An enzyme driven pathway is implemented to synthesize these key lipids. If these enzymes are down- or upregulated as in inflammatory diseases, the final lipid composition is affected often altering the barrier function. In this study, we mimicked down regulation of enzymes involved in the synthesis of the sphingosine and CER amide bond. In a LPP lipid model, we substituted CER N-(tetracosanoyl)-sphingosine (CER NS) with either i) FFA C24 and free sphingosine, to simulate the loss of the CER amide bond, or ii) with FFA C24 and C18 to simulate the loss of the sphingosine headgroup. Our study shows the lipids in the LPP would not phase separate until at least 25% of the CER NS is substituted keeping the lateral packing and conformational ordering unaltered. Neutron diffraction studies showed that free sphingosine chains localized at the outer layers of the unit cell, while the remaining CER NS head group was concentrated in the inner headgroup layers. However, when FFA C18 was inserted, CER NS was dispersed throughout the LPP, resulting in an even distribution between the inner and outer water layers. The presented results highlight the importance of the CER NS headgroup structure and its interaction in combination with the carbon chain invariability for optimal lipid arrangement.
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Affiliation(s)
- Charlotte M Beddoes
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, the Netherlands
| | - Gert S Gooris
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, the Netherlands
| | - David J Barlow
- Division of Pharmacy and Optometry, Manchester University, Manchester, United Kingdom
| | - M Jayne Lawrence
- Division of Pharmacy and Optometry, Manchester University, Manchester, United Kingdom
| | - Robert M Dalgliesh
- ISIS Neutron and Muon Source, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot OX11 0QX, United Kingdom
| | - Marc Malfois
- ALBA Synchrotron, Carrer de la Llum 2-6, 08290 Cerdanyola del Valles, Barcelona, Spain
| | - Bruno Demé
- Institut Laue-Langevin, Grenoble, France
| | - Joke A Bouwstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, the Netherlands.
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25
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Salgaonkar N, Kadamkode V, Kumaran S, Mallemala P, Christy E, Appavoo S, Majumdar A, Mitra R, Dasgupta A. Glycerol fermentation by skin bacteria generates lactic acid and upregulates the expression levels of genes associated with the skin barrier function. Exp Dermatol 2022; 31:1364-1372. [PMID: 35535416 DOI: 10.1111/exd.14604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 04/18/2022] [Accepted: 05/04/2022] [Indexed: 11/30/2022]
Abstract
Commensal bacteria play a major role in multiple skin functions by providing the first layer of defense against pathogens and maintaining the skin barrier. Staphylococcus epidermidis is one of the most common skin commensals. In this study, we showed that S. epidermidis ferments glycerol and uses it as a nutrient, while producing short-chain and organic fatty acids, with the most notable being lactic acid. Lactic acid is an alpha-hydroxy acid that inhibits the growth of pathogenic bacteria, without any negative effect on the commensal bacteria itself. Using in vivo experiments, we validated our in vitro results, showing that the skin microbiome is also capable of doing this. Finally, using 2D and 3D skin culture models, we showed that the fermentation of glycerol, mainly lactic acid, as determined by analytical methods, upregulates the expression levels of several key genes that are associated with the barrier properties of the skin. While the hydration effect of glycerol on the skin is well known, our study shows the overall benefits of glycerol on the skin microbiome, while revealing an alternate mode of action of glycerol for multiple skin benefits.
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Affiliation(s)
| | | | | | | | - Ernest Christy
- Unilever R&D, 64 Whitefield, Bangalore, Karnataka, India
| | | | | | - Rupak Mitra
- Unilever R&D, 64 Whitefield, Bangalore, Karnataka, India
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26
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Salimian J, Salehi Z, Ahmadi A, Emamvirdizadeh A, Davoudi SM, Karimi M, Korani M, Azimzadeh Jamalkandi S. Atopic dermatitis: molecular, cellular, and clinical aspects. Mol Biol Rep 2022; 49:3333-3348. [PMID: 34989960 DOI: 10.1007/s11033-021-07081-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 12/09/2021] [Indexed: 10/19/2022]
Abstract
Atopic dermatitis (AD) is a complicated, inflammatory skin disease, which numerous genetic and environmental factors play roles in its development. AD is categorized into different phenotypes and stages, although they are mostly similar in their pathophysiological aspects. Immune response alterations and structural distortions of the skin-barrier layer are evident in AD patients. Genetic makeup, lifestyle, and environment are also significantly involved in contextual factors. Genes involved in AD-susceptibility, including filaggrin and natural moisturizing, cause considerable structural modifications in the skin's lipid bilayer and cornified envelope. Additionally, the skin's decreased integrity and altered structure are accompanied by biochemical changes in the normal skin microflora's dysbiosis. The dynamic immunological responses, genetic susceptibilities, and structural modifications associated with AD's pathophysiology will be extensively discussed in this review, each according to the latest achievements and findings.
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Affiliation(s)
- Jafar Salimian
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Ahmadi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alireza Emamvirdizadeh
- Department of Genetics, Faculty of Bio Sciences, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Seyyed Masoud Davoudi
- Department of Dermatology, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehrdad Karimi
- Department of Traditional Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Korani
- Department of Biochemistry, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sadegh Azimzadeh Jamalkandi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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27
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Kordulewska N, Topa J, Cieślińska A, Jarmołowska B. Osthole Regulates Secretion of Pro-Inflammatory Cytokines and Expression of TLR2 and NF-κB in Normal Human Keratinocytes and Fibroblasts. J Inflamm Res 2022; 15:1501-1519. [PMID: 35261546 PMCID: PMC8898189 DOI: 10.2147/jir.s349216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/20/2022] [Indexed: 12/13/2022] Open
Affiliation(s)
- Natalia Kordulewska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
- Correspondence: Natalia Kordulewska, Tel + 48 89 523 37 63, Fax + 48 89 535 20 15, Email
| | - Justyna Topa
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdańsk, Gdańsk, Poland
| | - Anna Cieślińska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
| | - Beata Jarmołowska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
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28
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Kim K, Kim H, Sung GY. An Interleukin-4 and Interleukin-13 Induced Atopic Dermatitis Human Skin Equivalent Model by a Skin-On-A-Chip. Int J Mol Sci 2022; 23:ijms23042116. [PMID: 35216228 PMCID: PMC8878506 DOI: 10.3390/ijms23042116] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 01/30/2022] [Accepted: 02/08/2022] [Indexed: 12/27/2022] Open
Abstract
Currently, the mechanism of progression of atopic dermatitis (AD) is not well understood because there is no physiologically appropriate disease model in terms of disease complexity and multifactoriality. Type 2 inflammation, mediated by interleukin (IL)-4 and IL-13, plays an important role in AD. In this study, full-thickness human skin equivalents consisting of human-derived cells were fabricated from pumpless microfluidic chips and stimulated with IL-4 and IL-13. The morphological properties, gene expression, cytokine secretion and protein expression of the stimulated human skin equivalent (HSE) epidermis were investigated. The results showed epidermal and spongy formations similar to those observed in lesions in AD, and decreased expression of barrier-related filaggrin, loricrin and involucrin genes and proteins induced by IL-4Rα signaling. In addition, we induced the expression of carbonic anhydrase II (CAII), a gene specifically expressed in the epidermis of patients with AD. Thus, AD human skin equivalents can be used to mimic the key pathological features of atopic dermatitis, overcoming the limitations of existing studies that rely solely on mouse models and have been unable to translate their effects to humans. Our results will be useful for future research on the development of therapeutic agents for atopic dermatitis.
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Affiliation(s)
- Kyunghee Kim
- Interdisciplinary Program of Nano-Medical Device Engineering, Hallym University, Chuncheon 24252, Korea;
- Major in Materials Science and Engineering, Hallym University, Chuncheon 24252, Korea;
| | - Hyeju Kim
- Major in Materials Science and Engineering, Hallym University, Chuncheon 24252, Korea;
| | - Gun Yong Sung
- Interdisciplinary Program of Nano-Medical Device Engineering, Hallym University, Chuncheon 24252, Korea;
- Major in Materials Science and Engineering, Hallym University, Chuncheon 24252, Korea;
- Integrative Materials Research Institute, Hallym University, Chuncheon 24252, Korea
- Correspondence:
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29
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Oh JH, Hur W, Li N, Jo SJ. Effects of the epidermal growth factor receptor inhibitor, gefitinib, on lipid and hyaluronic acid synthesis in cultured HaCaT keratinocytes. Exp Dermatol 2022; 31:918-927. [PMID: 35122447 DOI: 10.1111/exd.14538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/30/2021] [Accepted: 02/02/2022] [Indexed: 11/30/2022]
Abstract
Epidermal growth factor receptor inhibitors (EGFRIs) are widely used for treating various cancers, including lung, colon, head and neck cancers. However, EGFRIs have unique dermatological side effects, including acneiform eruption, dry skin, paronychias, and pruritus. In this study, we investigated the molecular changes induced by an EGFRI, gefitinib, in the expression of lipogenic enzymes and hyaluronic acid (HA) regulatory proteins in HaCaT keratinocytes, and whether EGF restored these changes. HaCaT cells were treated with gefitinib, with or without EGF, and treated with tumor necrosis factor α (TNFα) for inducing an inflammatory response. The mRNA and protein expression was analyzed by real-time RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. Gefitinib enhanced the TNFα-induced expression of C-C motif chemokine ligand 2 (CCL2), CCL5, and C-X-C motif chemokine ligand 10 (CXCL10), and the expression of TNFα in HaCaT cells, while EGF restored these changes. At a similar concentration range, gefitinib reduced the mRNA and/or protein expression of various lipogenic enzymes for fatty acid, cholesterol, and ceramide synthesis, except acidic sphingomyelinase. Gefitinib suppressed the mRNA and protein expression of HA synthase 2 (HAS2), HAS3, cluster of differentiation 44 (CD44), hyaluronidase 1 (HYAL1), and HYAL2, except the mRNA expression of HYAL1. EGF restored the changes induced by gefitinib, except for the mRNA expression of fatty acid synthase (FASN) and elongation of very long chain fatty acids protein (ELOVL) 6. In conclusion, EGFRIs suppress lipogenesis and HA metabolism, which may contribute to adverse dermatological effects, including barrier function impairment in cancer patients treated with EGFRIs.
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Affiliation(s)
- Jang-Hee Oh
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Woojune Hur
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Na Li
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seong Jin Jo
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Cutaneous Aging Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Center for Skin Cancer and Adverse Skin Reaction to Chemotherapeutics, Seoul National University Cancer Hospital, Seoul, Republic of Korea
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30
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Amar Y, Schneider E, Köberle M, Seeholzer T, Musiol S, Hölge IM, Gschwendtner S, Krappmann D, Steiger K, Biedermann T, Schmidt-Weber CB, Alessandrini F. Microbial dysbiosis in a mouse model of atopic dermatitis mimics shifts in human microbiome and correlates with the key pro-inflammatory cytokines IL-4, IL-33 and TSLP. J Eur Acad Dermatol Venereol 2022; 36:705-716. [PMID: 35015907 DOI: 10.1111/jdv.17911] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/03/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cutaneous bacterial dysbiosis is a characteristic hallmark of atopic dermatitis (AD) and it decisively influences the severity of the disease. Despite this, frequently used murine models of AD have not been characterized regarding the changes in skin microbiome communities. OBJECTIVE To analyze the skin microbiome of two frequently used murine models for AD for assessing their applicability in translational research. METHODS AD was induced in mice by topical application of calcipotriol, or oxazolone. Following comparable elicitation of AD-like dermatitis, including IgE induction, the skin microbial communities were analyzed and compared with human AD. RESULTS We detected critical differences in the microbiota composition of diseased skin. In contrast to calcipotriol treatment, application of oxazolone induced significant changes of the cutaneous microbiota and a drastic drop of bacterial richness. Furthermore, an expansion of Staphylococci, particularly S. xylosus was observed in the oxazolone group, also displaying positive correlations with AD key markers including pH, TEWL, IL-4, TSLP and IL-33. CONCLUSIONS In this article we show that i) the model of choice to investigate AD needs to be characterized for the cutaneous microbiota if applicable and ii) the oxazolone-mediated mixed Th1-Th2 immune response triggers microbiota-induced alterations which share similarities to dysbiosis in human AD and represents therefore a suitable model for translational research on AD if alterations of the microbiome are in the focus of the investigation.
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Affiliation(s)
- Y Amar
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - E Schneider
- Center of Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Zentrum München, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - M Köberle
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - T Seeholzer
- Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Center München, German Research Center for Environmental Health, Neuherberg, Germany
| | - S Musiol
- Center of Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Zentrum München, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Munich, Germany.,Eurofins BioPharma Product Testing Munich GmbH, Planegg, Germany
| | - I M Hölge
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - S Gschwendtner
- Research Unit for Comparative Microbiome Analysis, Helmholtz Center München, German Research Center for Environmental Health, Neuherberg, Germany
| | - D Krappmann
- Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Center München, German Research Center for Environmental Health, Neuherberg, Germany
| | - K Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - T Biedermann
- Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany
| | - C B Schmidt-Weber
- Center of Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Zentrum München, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Munich, Germany
| | - F Alessandrini
- Center of Allergy & Environment (ZAUM), Technical University of Munich (TUM) and Helmholtz Zentrum München, German Research Center for Environmental Health, Member of the German Center of Lung Research (DZL), Munich, Germany
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31
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Matsuoka M, Okoshi K, Ito S, Kume T, Seki T, Nishizaka T, Okada J, Nagasawa A, Iijima M, Abe M, Nemoto O. Efficacy of Heparinoid Cream Containing Pseudo-Ceramide for Remission of Atopic Dermatitis. Clin Cosmet Investig Dermatol 2021; 14:1839-1847. [PMID: 34949930 PMCID: PMC8688830 DOI: 10.2147/ccid.s337930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Purpose Atopic dermatitis (AD) is characterized by chronic inflammation, which frequently recurs, is exacerbated, and enters remission. A maintenance remission period is important for AD patients. We developed a formulation for use during AD remission, containing heparinoid and pseudo-ceramide that forms a lamellar structure. We evaluated the allergen permeability and examined the formulation’s efficacy in maintaining remission in patients with AD. Materials and Methods Seventeen AD patients applied a cream containing 0.3% heparinoid and pseudo-ceramide (test cream group, n = 10), or a general cream containing 0.3% heparinoid (control cream group, n = 7) to their arm for four weeks after inducing remission with the application of a steroid cream for two weeks. Results The lamellar structure of the test cream was confirmed with small- and wide-angle x-ray scattering analysis and observation by transmission electron microscopy. The test cream inhibited the penetration of V8 protease significantly compared to the control cream in vitro. According to AD severity score by dermatologists, the effects remission maintenance of the test cream group were comparable to those of the control cream group. However, the test cream group had a significantly increased skin hydration value compared to the control cream group. A significant decrease in transepidermal water loss, an indicator of skin barrier function, was shown in the test cream group compared to the control cream group. Conclusion The cream with lamellar structures containing heparinoid and pseudo-ceramides may inhibit allergen penetration. Moreover, skin properties improved during the remission period; thus, the formulation we developed was suitable for use during the AD remission period.
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Affiliation(s)
- Megumi Matsuoka
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Keita Okoshi
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Shotaro Ito
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Takuji Kume
- Analytical Science Research, Kao Corporation, Wakayama, Japan
| | - Tsuyoshi Seki
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Takahiro Nishizaka
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Joji Okada
- Skin Care Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Azumi Nagasawa
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
| | - Makoto Iijima
- Health & Wellness Products Research, Kao Corporation, Sumida-ku, Tokyo, Japan
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32
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Hüppop F, Dähnhardt-Pfeiffer S, Fölster-Holst R. Characterization of Classical Flexural and Nummular Forms of Atopic Dermatitis in Childhood with Regard to Anamnestic, Clinical and Epidermal Barrier Aspects. Acta Derm Venereol 2021; 102:adv00664. [PMID: 34935994 DOI: 10.2340/actadv.v101.979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Nummular (coin-shaped) and classical (flexural) atopic dermatitis differ morphologically, but no other distinguishing features are known. The aim of this study was to determine differences and similarities of both variants in children. Detailed interviews, clinical examinations, biophysical measurements and electron microscopic analyses were performed on 10 children with nummular atopic dermatitis, 14 with classical atopic dermatitis and 10 healthy controls. Nummular atopic dermatitis affected more boys than girls and manifested less frequently within the first year of life than classical atopic dermatitis. Localization, distribution and morphology of the eczema varied more over time, and expression of keratosis pilaris was more severe in children with nummular atopic dermatitis. Both disease groups showed reduced hydration, increased transepidermal water loss and reduced intercellular lipid lamellae in lesional skin areas compared with non-lesional areas. These findings underline the separate classification of both variants. Further research is necessary to investigate the potential of diverging therapeutic approaches.
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Affiliation(s)
| | | | - Regina Fölster-Holst
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller Str. 3, DE-24105 Kiel, Germany.
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33
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Altgilbers S, Rippke F, Filbry A, Conzelmann S, Vietzke JP, Burkhardt T, Segger D, Roggenkamp D, Grönniger E. A Biomimetic Combination of Actives Enhances Skin Hydration and Barrier Function via Modulation of Gene Expression: Results of Two Double-Blind, Vehicle-Controlled Clinical Studies. Skin Pharmacol Physiol 2021; 35:102-111. [PMID: 34619676 DOI: 10.1159/000520009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/01/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Xerosis cutis is characterized by a decreased stratum corneum (SC) hydration and an impaired skin barrier function. Urea, the most prevalent natural moisturizing factor (NMF), is currently considered the gold standard. Its efficacy can further be increased by combining urea with other NMF and skin barrier lipids (SBLs). OBJECTIVE We set out to evaluate physiological effects of a novel functional moisturizer containing 10% urea, additional NMF components, and a combination of SBLs on skin hydration and skin barrier integrity on a cellular and phenotypic level in female volunteers suffering from xerosis. METHODS Two double-blind, vehicle-controlled clinical studies were conducted. In the first study, 44 female subjects having very dry body skin applied the moisturizer or its vehicle twice daily to their volar forearms. Twenty-four hours after a single product application as well as 24 h after 2 weeks of treatment, SC hydration was measured by corneometry. Skin barrier function was assessed by transepidermal water loss 24 h and 48 h after 2 weeks of regular use. Twenty-four hours after 2 weeks of application, skin tape stripping was performed, and urea content was determined in the 3rd strip by means of high-performance liquid chromatography/tandem mass spectrometry. In the second study, 22 women with self-reported very dry skin applied the moisturizer or vehicle twice daily to their volar forearms for 2 weeks. Then, suction blister samples were obtained for gene expression analysis using RT-PCR. RESULTS Application of the actives led to significantly improved skin hydration and barrier function at all points in time. Compared to the vehicle, application of the moisturizer for 2 weeks resulted in a significant increase in SC urea content. Relative gene expression data revealed significant upregulation of genes associated with skin barrier function, hydration, differentiation, and lipid metabolism compared to the vehicle-treated area. CONCLUSIONS Overall, our data demonstrate that the functional moisturizer provides an adequate bioavailability of urea and a beneficial biophysical impact on xerotic skin. Topical treatment with a combination of urea and additional NMF as well as SBL can modify mRNA expression of important epidermal genes stimulating cellular processes and functions. The well-tolerated novel functional moisturizer stimulates molecular mechanisms involved in skin hydration and barrier function and is a profoundly effective treatment option for xerosis cutis.
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Affiliation(s)
| | - Frank Rippke
- Research and Development, Beiersdorf AG, Hamburg, Germany
| | | | | | | | | | - Dörte Segger
- SGS Institut Fresenius GmbH (former SIT Skin Investigation and Technology), Hamburg, Germany
| | | | - Elke Grönniger
- Research and Development, Beiersdorf AG, Hamburg, Germany
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34
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Fölster-Holst R, Reimer R, Neumann C, Proksch E, Rodriguez E, Weidinger S, Goldust M, Hanisch E, Dähnhardt-Pfeiffer S, Freitag-Wolf S. Comparison of Epidermal Barrier Integrity in Adults with Classic Atopic Dermatitis, Atopic Prurigo and Non-Atopic Prurigo Nodularis. BIOLOGY 2021; 10:1008. [PMID: 34681107 PMCID: PMC8533604 DOI: 10.3390/biology10101008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/26/2021] [Accepted: 10/02/2021] [Indexed: 12/20/2022]
Abstract
A deficient epidermal barrier is a key feature of atopic dermatitis (AD) and comprises altered lipid and protein content and composition of the stratum corneum resulting in disturbed water balance. Clinically, eczematous lesions on dry skin and pruritus develop. Pruritic nodules occur in prurigo nodularis (PN), another chronic skin disease, which can be associated with atopy. We aimed at comparing the three clinical pictures, classic AD, atopic prurigo (AP), and non-atopic PN, to healthy controls regarding the epidermal barrier. We determined clinical parameters and performed biophysical measurements, histology/immunohistochemistry, electron microscopy, and molecular biological analysis. We found distinctively elevated clinical scores, reduced hydration and increased transepidermal water loss, epidermal hyperplasia and inflammation reduced filaggrin and increased loricrin and involucrin expression, as well as reduced intercellular lipid lamellae in all three disease groups. These findings show a severe disruption in epidermal barrier structure and function in all three disorders so that epidermal barrier impairment is now proven not only for AD but also for PN.
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Affiliation(s)
- Regina Fölster-Holst
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (C.N.); (E.P.); (E.R.); (S.W.)
| | - Rahel Reimer
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (C.N.); (E.P.); (E.R.); (S.W.)
| | - Claudia Neumann
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (C.N.); (E.P.); (E.R.); (S.W.)
| | - Erhardt Proksch
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (C.N.); (E.P.); (E.R.); (S.W.)
| | - Elke Rodriguez
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (C.N.); (E.P.); (E.R.); (S.W.)
| | - Stephan Weidinger
- Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (C.N.); (E.P.); (E.R.); (S.W.)
| | - Mohamad Goldust
- Department of Dermatology, University Medical Center Mainz, 55101 Mainz, Germany;
| | | | | | - Sandra Freitag-Wolf
- Institute of Medical Informatics and Statistics, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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35
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Fujii M. The Pathogenic and Therapeutic Implications of Ceramide Abnormalities in Atopic Dermatitis. Cells 2021; 10:2386. [PMID: 34572035 PMCID: PMC8468445 DOI: 10.3390/cells10092386] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 11/16/2022] Open
Abstract
Ceramides play an essential role in forming a permeability barrier in the skin. Atopic dermatitis (AD) is a common chronic skin disease associated with skin barrier dysfunction and immunological abnormalities. In patients with AD, the amount and composition of ceramides in the stratum corneum are altered. This suggests that ceramide abnormalities are involved in the pathogenesis of AD. The mechanism underlying lipid abnormalities in AD has not yet been fully elucidated, but the involvement of Th2 and Th1 cytokines is implicated. Ceramide-dominant emollients have beneficial effects on skin barrier function; thus, they have been approved as an adjunctive barrier repair agent for AD. This review summarizes the current understanding of the mechanisms of ceramide abnormalities in AD. Furthermore, the potential therapeutic approaches for correcting ceramide abnormalities in AD are discussed.
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Affiliation(s)
- Masanori Fujii
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
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36
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Voorberg AN, Niehues H, Oosterhaven JAF, Romeijn GLE, van Vlijmen-Willems IMJJ, van Erp PEJ, Ederveen THA, Zeeuwen PLJM, Schuttelaar MLA. Vesicular hand eczema transcriptome analysis provides insights into its pathophysiology. Exp Dermatol 2021; 30:1775-1786. [PMID: 34252224 PMCID: PMC8596617 DOI: 10.1111/exd.14428] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/18/2021] [Accepted: 07/06/2021] [Indexed: 12/15/2022]
Abstract
Hand eczema is a common inflammatory skin condition of the hands whose pathogenesis is largely unknown. More insight and knowledge of the disease on a more fundamental level might lead to a better understanding of the biological processes involved, which could provide possible new treatment strategies. We aimed to profile the transcriptome of lesional palmar epidermal skin of patients suffering from vesicular hand eczema using RNA‐sequencing. RNA‐sequencing was performed to identify differentially expressed genes in lesional vs. non‐lesional palmar epidermal skin from a group of patients with vesicular hand eczema compared to healthy controls. Comprehensive real‐time quantitative PCR analyses and immunohistochemistry were used for validation of candidate genes and protein profiles for vesicular hand eczema. Overall, a significant and high expression of genes/proteins involved in keratinocyte host defense and inflammation was found in lesional skin. Furthermore, we detected several molecules, both up or downregulated in lesional skin, which are involved in epidermal differentiation. Immune signalling genes were found to be upregulated in lesional skin, albeit with relatively low expression levels. Non‐lesional patient skin showed no significant differences compared to healthy control skin. Lesional vesicular hand eczema skin shows a distinct expression profile compared to non‐lesional skin and healthy control skin. Notably, the overall results indicate a large overlap between vesicular hand eczema and earlier reported atopic dermatitis lesional transcriptome profiles, which suggests that treatments for atopic dermatitis could also be effective in (vesicular) hand eczema.
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Affiliation(s)
- Angelique N Voorberg
- Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hanna Niehues
- Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, The Netherlands
| | - Jart A F Oosterhaven
- Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Geertruida L E Romeijn
- Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ivonne M J J van Vlijmen-Willems
- Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, The Netherlands
| | - Piet E J van Erp
- Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, The Netherlands
| | - Thomas H A Ederveen
- Center for Molecular and Biomolecular Informatics, RIMLS, Radboudumc, Nijmegen, The Netherlands
| | - Patrick L J M Zeeuwen
- Department of Dermatology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, The Netherlands
| | - Marie L A Schuttelaar
- Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Kanwal S, Singh SK, Soman SP, Choudhury S, Kumari P, Ram PK, Garg SK. Expression of barrier proteins in the skin lesions and inflammatory cytokines in peripheral blood mononuclear cells of atopic dogs. Sci Rep 2021; 11:11418. [PMID: 34075152 PMCID: PMC8169657 DOI: 10.1038/s41598-021-90992-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/19/2021] [Indexed: 01/31/2023] Open
Abstract
Atopic dermatitis (AD) is one of the most common skin diseases of dogs. Defects in the skin barrier and overproduction of inflammatory cytokines may be the pathogenesis of canine AD. Therefore, the present study was aimed to quantify the gene expression of certain skin barrier proteins and inflammatory cytokines in dogs with AD. Eleven dogs with AD and three healthy dogs were included in the present study. The skin barrier proteins, namely Filaggrin (FLG) and Involucrin (IVL), gene expression was quantified by Real-time PCR in the lesional skin tissues of the atopic dogs and normal skin of the healthy dogs. In addition to the skin proteins, the gene expressions of the interleukin (IL)-13, IL-31, and tumour necrosis factor (TNF)-α were also quantified in the peripheral blood mononuclear cells (PBMCs) of these dogs. Compared to the healthy dogs, significantly higher (P ≤ 0.01) FLG gene expression and significantly (P ≤ 0.05) lower expression of the IVL gene were quantified in the skin of atopic dogs. Further, the dogs with AD revealed significantly higher expression of TNF-α (P ≤ 0.01), IL-31 (P ≤ 0.05), and IL-13 (P ≤ 0.05) as compared to the healthy dogs. The findings of our present study evidently suggest significantly increased and decreased expressions of FLG and IVL genes, respectively, which may be responsible for disruption of the skin barrier in dogs with AD. While, the over-expressions of TNF-α, IL-31, and IL-13 genes might be attributed to the clinical pathology and manifestations of AD in dogs. However, further studies are warranted to substantiate our hypothesis about pathogenesis and clinical manifestation of AD in dogs by including a large number of animals.
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Affiliation(s)
- Sarita Kanwal
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India
| | - Shanker K Singh
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India.
| | - Sandeep P Soman
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India
| | - Soumen Choudhury
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India
| | - Priyambada Kumari
- College of Biotechnology, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India
| | - Pradeep K Ram
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India
| | - Satish K Garg
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, Uttar Pradesh Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sanstahan (DUVASU), Mathura, U.P., 281 001, India
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38
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Luger T, Amagai M, Dreno B, Dagnelie MA, Liao W, Kabashima K, Schikowski T, Proksch E, Elias PM, Simon M, Simpson E, Grinich E, Schmuth M. Atopic dermatitis: Role of the skin barrier, environment, microbiome, and therapeutic agents. J Dermatol Sci 2021; 102:142-157. [PMID: 34116898 DOI: 10.1016/j.jdermsci.2021.04.007] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023]
Abstract
Atopic dermatitis (AD) is a chronic, inflammatory skin disorder characterized by eczematous and pruritic skin lesions. In recent decades, the prevalence of AD has increased worldwide, most notably in developing countries. The enormous progress in our understanding of the complex composition and functions of the epidermal barrier allows for a deeper appreciation of the active role that the skin barrier plays in the initiation and maintenance of skin inflammation. The epidermis forms a physical, chemical, immunological, neuro-sensory, and microbial barrier between the internal and external environment. Not only lesional, but also non-lesional areas of AD skin display many morphological, biochemical and functional differences compared with healthy skin. Supporting this notion, genetic defects affecting structural proteins of the skin barrier, including filaggrin, contribute to an increased risk of AD. There is evidence to suggest that natural environmental allergens and man-made pollutants are associated with an increased likelihood of developing AD. A compromised epidermal barrier predisposes the skin to increased permeability of these compounds. Numerous topical and systemic therapies for AD are currently available or in development; while anti-inflammatory therapy is central to the treatment of AD, some existing and novel therapies also appear to exert beneficial effects on skin barrier function. Further research on the skin barrier, particularly addressing epidermal differentiation and inflammation, lipid metabolism, and the role of bacterial communities for skin barrier function, will likely expand our understanding of the complex etiology of AD and lead to identification of novel targets and the development of new therapies.
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Affiliation(s)
- Thomas Luger
- Department of Dermatology, University of Münster, Münster, Germany.
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Brigitte Dreno
- Dermatology Department, Nantes University, CHU Nantes, CIC 1413, CRCINA, Nantes, France
| | - Marie-Ange Dagnelie
- Dermatology Department, Nantes University, CHU Nantes, CIC 1413, CRCINA, Nantes, France
| | - Wilson Liao
- Department of Dermatology, University of California, San Francisco, CA, United States
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tamara Schikowski
- IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
| | | | - Peter M Elias
- San Francisco VA Medical Center, University of California, San Francisco, CA, United States
| | - Michel Simon
- UDEAR, Inserm, University of Toulouse, U1056, Toulouse, France
| | - Eric Simpson
- Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
| | - Erin Grinich
- Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
| | - Matthias Schmuth
- Department of Dermatology, Medical University Innsbruck, Innsbruck, Austria
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Leung DYM, Berdyshev E, Goleva E. Cutaneous barrier dysfunction in allergic diseases. J Allergy Clin Immunol 2021; 145:1485-1497. [PMID: 32507227 DOI: 10.1016/j.jaci.2020.02.021] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 01/08/2023]
Abstract
The fundamental defect(s) that drives atopic dermatitis (AD) remains controversial. "Outside in" proponents point to the important association of filaggrin gene mutations and other skin barrier defects with AD. The "inside out" proponents derive support from evidence that AD occurs in genetic animal models with overexpression of type 2 immune pathways in their skin, and humans with gain-of-function mutations in their type 2 response develop severe AD. The observation that therapeutic biologics, targeting type 2 immune responses, can reverse AD provides compelling support for the importance of "inside out" mechanisms of AD. In this review, we propose a central role for epithelial cell dysfunction that accounts for the dual role of skin barrier defects and immune pathway activation in AD. The complexity of AD has its roots in the dysfunction of the epithelial barrier that allows the penetration of allergens, irritants, and microbes into a cutaneous milieu that facilitates the induction of type 2 immune responses. The AD phenotypes and endotypes that result in chronic skin inflammation and barrier dysfunction are modified by genes, innate/adaptive immune responses, and different environmental factors that cause skin barrier dysfunction. There is also compelling evidence that skin barrier dysfunction can alter the course of childhood asthma, food allergy, and allergic rhinosinusitis. Effective management of AD requires a multipronged approach, not only restoring cutaneous barrier function, microbial flora, and immune homeostasis but also enhancing skin epithelial differentiation.
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Affiliation(s)
| | | | - Elena Goleva
- Department of Pediatrics, National Jewish Health, Denver, Colo
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Quadri M, Lotti R, Bonzano L, Ciardo S, Guanti MB, Pellacani G, Pincelli C, Marconi A. A Novel Multi-Action Emollient Plus Cream Improves Skin Barrier Function in Patients with Atopic Dermatitis: In vitro and Clinical Evidence. Skin Pharmacol Physiol 2021; 34:8-18. [PMID: 33601378 DOI: 10.1159/000513055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 11/13/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Emollients capable of restoring the skin barrier function would extend their role beyond basic maintenance therapy in atopic dermatitis (AD). OBJECTIVES Investigate the effect of a novel emollient plus cream (EC; Dermoflan®) on the skin barrier in vitro and in patients with mild-to-moderate AD. METHODS The effect of EC on the skin barrier recovery was evaluated using a tape-stripping (TS) model. After TS, organ cultures were treated with EC (undiluted or diluted 1:1 with water) and analyzed at 18-120 h using hematoxylin and eosin, Oil Red O, immunohistochemical, and immunofluorescent techniques. In a double-blind, randomized study, EC or placebo was applied once daily for 2 months to antecubital folds of the upper and lower limbs of patients with mild-to-moderate AD in clinical remission. Epidermal thickness, vascularization, and epidermal hydration were assessed by optical coherence tomography and corneometry, respectively, at baseline, and 1 and 2 months following treatment initiation. RESULTS Following TS, EC treatment significantly increased epidermal thickness and lipid content versus diluent in the skin organ culture, as well as claudin-1, involucrin, and caspase-14 expression, suggesting skin barrier repair. EC treatment also decreased keratin-16 expression and increased levels of Toll-like receptors 1 and 2 versus diluent, suggesting involvement in regulating the epidermal immune response. In 20 patients randomized 1:1 to EC or placebo, EC treatment at the elbow fold/popliteal fossa significantly decreased epidermal thickness after 2 months, and the number of blood vessels at the elbow fold after 1 and 2 months, versus placebo. EC significantly improved the skin hydration after 2 months versus baseline. CONCLUSIONS This novel multi-action EC may help to restore epidermal homeostasis and improve the skin of patients with AD. Results indicate that this novel multi-action EC could be a valid adjuvant therapy in patients with AD. Key Message: Novel multi-action emollient cream helps to restore epidermal homeostasis and improves the skin affected by AD.
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Affiliation(s)
- Marika Quadri
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermolab, University of Modena and Reggio Emilia, Modena, Italy,
| | - Roberta Lotti
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermolab, University of Modena and Reggio Emilia, Modena, Italy
| | - Laura Bonzano
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvana Ciardo
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Mario Bruno Guanti
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Giovanni Pellacani
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Pincelli
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermolab, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Marconi
- Department of Surgical, Medical, Dental, and Morphological Sciences, Dermolab, University of Modena and Reggio Emilia, Modena, Italy
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Franco LAM, Moreira CHV, Buss LF, Oliveira LC, Martins RCR, Manuli ER, Lindoso JAL, Busch MP, Pereira AC, Sabino EC. Pharmacogenomic Profile and Adverse Drug Reactions in a Prospective Therapeutic Cohort of Chagas Disease Patients Treated with Benznidazole. Int J Mol Sci 2021; 22:ijms22041960. [PMID: 33669428 PMCID: PMC7920452 DOI: 10.3390/ijms22041960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/17/2020] [Accepted: 12/28/2020] [Indexed: 11/16/2022] Open
Abstract
Chagas disease remains a major social and public health problem in Latin America. Benznidazole (BZN) is the main drug with activity against Trypanosoma cruzi. Due to the high number of adverse drug reactions (ADRs), BZN is underprescribed. The goal of this study was to evaluate the genetic and transcriptional basis of BZN adverse reactions. Methods: A prospective cohort with 102 Chagas disease patients who underwent BZN treatment was established to identify ADRs and understand their genetic basis. The patients were classified into two groups: those with at least one ADR (n = 73), and those without ADRs (n = 29). Genomic analyses were performed comparing single nucleotide polymorphisms between groups. Transcriptome data were obtained comparing groups before and after treatment, and signaling pathways related to the main ADRs were evaluated. Results: A total of 73 subjects (71.5%) experienced ADRs. Dermatological symptoms were most frequent (45.1%). One region of chromosome 16, at the gene LOC102724084 (rs1518601, rs11861761, and rs34091595), was associated with ADRs (p = 5.652 × 10−8). Transcriptomic data revealed three significantly enriched signaling pathways related to BZN ADRs. Conclusions: These data suggest that part of adverse BZN reactions might be genetically determined and may facilitate patient risk stratification prior to starting BZN treatment.
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Affiliation(s)
- Lucas A. M. Franco
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
- Correspondence: (L.A.M.F.); (C.H.V.M.); Tel.: +55-11-3061-7042 (L.A.M.F. & C.H.V.M.)
| | - Carlos H. V. Moreira
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
- Institute of Infectology Emílio Ribas, São Paulo 01246-900, Brazil;
- Correspondence: (L.A.M.F.); (C.H.V.M.); Tel.: +55-11-3061-7042 (L.A.M.F. & C.H.V.M.)
| | - Lewis F. Buss
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
| | - Lea C. Oliveira
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
| | - Roberta C. R. Martins
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
| | - Erika R. Manuli
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
| | | | - Michael P. Busch
- Blood Systems Research Institute, San Francisco, CA 94118, USA;
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Alexandre C. Pereira
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA;
- Laboratory of Genetics and Molecular Cardiology, The Heart Institute, University of São Paulo, São Paulo 05403-000, Brazil
| | - Ester C. Sabino
- Department of Infectious Disease and Institute of Tropical Medicine (IMT-SP), University of São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo 05403-000, Brazil; (L.F.B.); (L.C.O.); (R.C.R.M.); (E.R.M.); (E.C.S.)
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Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase, the Enzyme Involved in Its Ceramide Deficiency, Plays a Pivotal Role. Int J Mol Sci 2021; 22:ijms22041613. [PMID: 33562655 PMCID: PMC7916095 DOI: 10.3390/ijms22041613] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/25/2022] Open
Abstract
Atopic dermatitis (AD) is characterized clinically by severe dry skin and functionally by both a cutaneous barrier disruption and an impaired water-holding capacity in the stratum corneum (SC) even in the nonlesional skin. The combination of the disrupted barrier and water-holding functions in nonlesional skin is closely linked to the disease severity of AD, which suggests that the barrier abnormality as well as the water deficiency are elicited as a result of the induced dermatitis and subsequently trigger the recurrence of dermatitis. These functional abnormalities of the SC are mainly attributable to significantly decreased levels of total ceramides and the altered ceramide profile in the SC. Clinical studies using a synthetic pseudo-ceramide (pCer) that can function as a natural ceramide have indicated the superior clinical efficacy of pCer and, more importantly, have shown that the ceramide deficiency rather than changes in the ceramide profile in the SC of AD patients plays a central role in the pathogenesis of AD. Clinical studies of infants with AD have shown that the barrier disruption due to the ceramide deficiency is not inherent and is essentially dependent on postinflammatory events in those infants. Consistently, the recovery of trans-epidermal water loss after tape-stripping occurs at a significantly slower rate only at 1 day post-tape-stripping in AD skin compared with healthy control (HC) skin. This resembles the recovery pattern observed in Niemann-Pick disease, which is caused by an acid sphingomyelinase (aSMase) deficiency. Further, comparison of ceramide levels in the SC between before and after tape-stripping revealed that whereas ceramide levels in HC skin are significantly upregulated at 4 days post-tape-stripping, their ceramide levels remain substantially unchanged at 4 days post-tape-stripping. Taken together, the sum of these findings strongly suggests that an impaired homeostasis of a ceramide-generating process may be associated with these abnormalities. We have discovered a novel enzyme, sphingomyelin (SM) deacylase, which cleaves the N-acyl linkage of SM and glucosylceramide (GCer). The activity of SM deacylase is significantly increased in AD lesional epidermis as well as in the involved and uninvolved SC of AD skin, but not in the skin of patients with contact dermatitis or chronic eczema, compared with HC skin. SM deacylase competes with aSMase and β-glucocerebrosidase (BGCase) to hydrolyze their common substrates, SM and GCer, to yield their lysoforms sphingosylphosphorylcholine (SPC) and glucosylsphingosine (GSP), respectively, instead of ceramide. Consistently, those reaction products (SPC and GSP) accumulate to a greater extent in the involved and uninvolved SC of AD skin compared with chronic eczema or contact dermatitis skin as well as HC skin. Successive chromatographies were used to purify SM deacylase to homogeneity with a single band of ≈43 kDa and with an enrichment of >14,000-fold. Analysis of a protein spot with SM deacylase activity separated by 2D-SDS-PAGE using MALDI-TOF MS/MS allowed its amino acid sequence to be determined and to identify it as the β-subunit of acid ceramidase (aCDase), an enzyme consisting of α- and β-subunits linked by amino-bonds and a single S-S bond. Western blotting of samples treated with 2-mercaptoethanol revealed that whereas recombinant human aCDase was recognized by antibodies to the α-subunit at ≈56 and ≈13 kDa and the β-subunit at ≈43 kDa, the purified SM deacylase was detectable only by the antibody to the β-subunit at ≈43 kDa. Breaking the S-S bond of recombinant human aCDase with dithiothreitol elicited the activity of SM deacylase with an apparent size of ≈40 kDa upon gel chromatography in contrast to aCDase activity with an apparent size of ≈50 kDa in untreated recombinant human aCDase. These results provide new insights into the essential role of SM deacylase as the β-subunit aCDase that causes the ceramide deficiency in AD skin.
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Profiling transcriptomic changes and signaling pathways in atopic dermatitis by integrative analyses on multiple databases. Mol Genet Genomics 2021; 296:341-353. [DOI: 10.1007/s00438-020-01754-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022]
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44
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Role of the Permeability Barrier in Contact Dermatitis. Contact Dermatitis 2021. [DOI: 10.1007/978-3-030-36335-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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45
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Jiménez M, Muñoz FC, Cervantes-García D, Cervantes MM, Hernández-Mercado A, Barrón-García B, Moreno Hernández-Duque JL, Rodríguez-Carlos A, Rivas-Santiago B, Salinas E. Protective Effect of Glycomacropeptide on the Atopic Dermatitis-Like Dysfunctional Skin Barrier in Rats. J Med Food 2020; 23:1216-1224. [DOI: 10.1089/jmf.2019.0247] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Mariela Jiménez
- Department of Microbiology, Autonomous University of Aguascalientes, Aguascalientes, México
| | - Fabiola C. Muñoz
- Department of Microbiology, Autonomous University of Aguascalientes, Aguascalientes, México
| | - Daniel Cervantes-García
- Department of Microbiology, Autonomous University of Aguascalientes, Aguascalientes, México
- National Council of Science and Technology, Mexico City, México
| | - Maritza M. Cervantes
- Department of Microbiology, Autonomous University of Aguascalientes, Aguascalientes, México
| | | | - Berenice Barrón-García
- Department of Microbiology, Autonomous University of Aguascalientes, Aguascalientes, México
| | | | - Adrián Rodríguez-Carlos
- Medical Research Unit from Zacatecas, Mexican Institute of Social Security, Zacatecas, México
| | - Bruno Rivas-Santiago
- Medical Research Unit from Zacatecas, Mexican Institute of Social Security, Zacatecas, México
| | - Eva Salinas
- Department of Microbiology, Autonomous University of Aguascalientes, Aguascalientes, México
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Dietary ceramide 2-aminoethylphosphonate, a marine sphingophosphonolipid, improves skin barrier function in hairless mice. Sci Rep 2020; 10:13891. [PMID: 32807849 PMCID: PMC7431532 DOI: 10.1038/s41598-020-70888-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 08/03/2020] [Indexed: 12/02/2022] Open
Abstract
Sphingolipids are one of the major components of cell membranes and are ubiquitous in eukaryotic organisms. Ceramide 2-aminoethylphosphonate (CAEP) of marine origin is a unique and abundant sphingophosphonolipid with a C-P bond. Although molluscs such as squids and bivalves, containing CAEP, are consumed globally, the dietary efficacy of CAEP is not understood. We investigated the efficacy of marine sphingophosphonolipids by studying the effect of dietary CAEP on the improvement of the skin barrier function in hairless mice fed a diet that induces severely dry-skin condition. The disrupted skin barrier functions such as an increase in the transepidermal water loss (TEWL), a decrease in the skin hydration index, and epidermal hyperplasia were restored by CEAP dietary supplementation. Correspondingly, dietary CAEP significantly increased the content of covalently bound ω-hydroxyceramide, and the expression of its biosynthesis-related genes in the skin. These effects of dietary CAEP mimic those of dietary plant glucosylceramide. The novel observations from this study show an enhancement in the skin barrier function by dietary CAEP and the effects could be contributed by the upregulation of covalently bound ω-hydroxyceramide synthesis in the skin.
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47
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Furue M. Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis. Int J Mol Sci 2020; 21:E5382. [PMID: 32751111 PMCID: PMC7432778 DOI: 10.3390/ijms21155382] [Citation(s) in RCA: 226] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022] Open
Abstract
Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.
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Affiliation(s)
- Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; ; Tel.: +81-92-642-5581; Fax: +81-92-642-5600
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
- Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
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Eberlin S, Silva MSD, Facchini G, Silva GHD, Pinheiro ALTA, Eberlin S, Pinheiro ADS. The Ex Vivo Skin Model as an Alternative Tool for the Efficacy and Safety Evaluation of Topical Products. Altern Lab Anim 2020; 48:10-22. [DOI: 10.1177/0261192920914193] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The development of alternative approaches for safety and efficacy testing that avoid the use of animals is a worldwide trend, which relies on the improvement of current models and tools so that they better reproduce human biology. Human skin from elective plastic surgery is a promising experimental model to test the effects of topically applied products. As the structure of native skin is maintained, including cell population (keratinocytes, melanocytes, Langerhans cells and fibroblasts) and dermal matrix (containing collagen, elastin, glycosaminoglycans, etc.), it most closely matches the effects of substances on in vivo human skin. In this review, we present a collection of results that our group has generated over the last years, involving the use of human skin and scalp explants, demonstrating the feasibility of this model. The development of a test system with ex vivo skin explants, of standard size and thickness, and cultured at the air–liquid interface, can provide an important tool for understanding the mechanisms involved in several cutaneous disorders.
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van Smeden J, Al-Khakany H, Wang Y, Visscher D, Stephens N, Absalah S, Overkleeft HS, Aerts JMFG, Hovnanian A, Bouwstra JA. Skin barrier lipid enzyme activity in Netherton patients is associated with protease activity and ceramide abnormalities. J Lipid Res 2020; 61:859-869. [PMID: 32265319 PMCID: PMC7269766 DOI: 10.1194/jlr.ra120000639] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/31/2020] [Indexed: 12/17/2022] Open
Abstract
Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum (SC) ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, β-glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) SC ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in SC ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered SC ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS.
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Affiliation(s)
- Jeroen van Smeden
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Centre for Human Drug Research, Leiden, The Netherlands
| | - Hanin Al-Khakany
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Yichen Wang
- INSERM UMR1163, Imagine Institute, Paris Descartes University, Paris, France
| | - Dani Visscher
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Nicole Stephens
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Samira Absalah
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Herman S Overkleeft
- Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Johannes M F G Aerts
- Medical Biochemistry Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Alain Hovnanian
- INSERM UMR1163, Imagine Institute, Paris Descartes University, Paris, France; Department of Genetics Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
| | - Joke A Bouwstra
- Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. mailto:
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Kurosaki Y, Tsurumachi M, Kamata Y, Tominaga M, Suga Y, Takamori K. Effects of 308 nm excimer light treatment on the skin microbiome of atopic dermatitis patients. PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE 2020; 36:185-191. [PMID: 31880842 DOI: 10.1111/phpp.12531] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/10/2019] [Accepted: 12/16/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND The skin microbiome has been implicated in the pathophysiology of atopic dermatitis (AD). Although 308 nm excimer light treatment is an effective phototherapy for AD, its effects on the skin microbiome currently remain unclear. Therefore, we investigated the effects of the excimer light treatment on the skin bacterial and fungal microbiome of lesional skin of AD. METHODS Swab samples were collected from 11 healthy controls, non-lesional and lesional skin of 11 AD patients. The excimer light treatment was administered to the lesional skin. The composition of the skin microbiome, the clinical score and skin barrier function of the lesional skin were examined before and after the treatment. The composition of the skin microbiome was determined by sequencing bacterial 16S and fungal internal transcribed spacer regions. RESULTS The excimer light treatment significantly changed the composition of the bacterial microbiome in the lesional skin of AD, as well as improved the clinical score and skin barrier function. The treatment increased the relative abundance of the phylum Cyanobacteria and decreased that of the phylum Bacteroidetes in lesional skin. At the species level, the treatment significantly decreased the relative abundance of Staphylococcus aureus (S aureus) in lesional skin. There was also a significant correlation between the reduction of S aureus and improvement of the clinical outcomes. CONCLUSION Our findings suggest that alterations of the skin microbiome with excimer light treatment, specifically the decrease in the abundance of S aureus, are partly involved in the improvement of AD lesions.
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Affiliation(s)
- Yuko Kurosaki
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Japan
- Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan
| | - Munehiro Tsurumachi
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Japan
- Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan
| | - Yayoi Kamata
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Japan
| | - Mitsutoshi Tominaga
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Japan
| | - Yasushi Suga
- Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan
| | - Kenji Takamori
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Japan
- Department of Dermatology, Juntendo University Urayasu Hospital, Urayasu, Japan
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