87 results on '"Schalkwijk, J."'
Search Results
2. 434 Molecular events in the epidermis upon aryl hydrocarbon receptor targeting: AHR-TFAP2A axis drives epidermal keratinocyte differentiation
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Smits, J.P., primary, Qu, J., additional, Pardow, F., additional, Rodijk-Olthuis, D., additional, van Vlijmen-Willems, I., additional, van Heeringen, S., additional, Zeeuwen, P., additional, Schalkwijk, J., additional, Zhou, H., additional, and van den Bogaard, E., additional
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- 2022
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3. 120 Identification of keratinocyte mitogens: implications for hyperproliferation in psoriasis and atopic dermatitis
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Niehues, H., primary, Rikken, G., additional, van Vlijmen-Willems, I.M., additional, Rodijk-Olthuis, D., additional, Erp, Pv, additional, Zeeuwen, P.L., additional, Schalkwijk, J., additional, and van den Bogaard, E.H., additional
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- 2021
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4. 172 CYSRT1: an antimicrobial epidermal protein that interacts with late cornified envelope (LCE) proteins
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Niehues, H., Rikken, G., Kersten, F., Eeftens, J., Oortveld, M., D van der krieken, Jansen, P., van Vlijmen-Willems, I.M., Smits, J.P., van den Brink, N., Hendriks, W., Ederveen, T., Schalkwijk, J., Zeeuwen, P.L., and van den Bogaard, E.H.
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- 2022
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5. 189 STAT1 gain-of-function compromises skin host defense in the context of IFN-γ signaling
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Niehues, H., primary, Rösler, B., additional, van der Krieken, D., additional, van Vlijmen-Willems, I., additional, Rodijk-Olthuis, D., additional, Peppelman, M., additional, Schalkwijk, J., additional, Zeeuwen, P., additional, van den Bogaard, E., additional, and van de Veerdonk, F., additional
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- 2019
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6. 191 Aryl hydrocarbon receptor controls epidermal differentiation and host defense response by regulation of AP1/AP2 transcription factor expression
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Smits, J., primary, Qu, J., additional, Rodijk-Olthuis, D., additional, van Vlijmen-Willems, I., additional, Zeeuwen, P., additional, Schalkwijk, J., additional, Zhou, J., additional, and van den Bogaard, E., additional
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- 2019
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7. 214 TARgeting the cutaneous microbiota in atopic dermatitis by coal tar via AHR-dependent induction of antimicrobial peptides
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Smits, J., primary, Ederveen, T., additional, Rikken, G., additional, van den Brink, N., additional, van Vlijmen-Willems, I., additional, Boekhorst, J., additional, Kamsteeg, M., additional, Schalkwijk, J., additional, van Hijum, S., additional, Zeeuwen, P., additional, and van den Bogaard, E., additional
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- 2019
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8. 190 Deficiency of the Human Cysteine Protease Inhibitor Cystatin M/E Causes Hypotrichosis and Dry Skin
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Zeeuwen, P., primary, van den Bogaard, E., additional, van Geel, M., additional, van Vlijmen-Willems, I., additional, Jansen, P., additional, van Erp, P., additional, Venselaar, H., additional, Joosten, M., additional, and Schalkwijk, J., additional
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- 2019
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9. Psoriasis-Associated Late Cornified Envelope (LCE) Proteins Have Antibacterial Activity
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Niehues, H., Tsoi, L.C., Krieken, D.A. van der, Jansen, P.A.M., Oortveld, M.A.W., Rodijk-Olthuis, D., Vlijmen, I.M.J.J. van, Hendriks, W.J.A.J., Helder, R.W.J., Bouwstra, J.A., Bogaard, E.H. van den, Stuart, P.E., Nair, R.P., Elder, J.T., Zeeuwen, P.L.J.M., Schalkwijk, J., Krieken, D. A. van der, Oortveld, M.A.W, Krieken, D. A. van der, and Oortveld, M.A.W
- Subjects
Keratinocytes ,Male ,0301 basic medicine ,Genotype ,Human skin ,Dermatology ,Quantitative trait locus ,Biology ,Real-Time Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Biochemistry ,Linkage Disequilibrium ,Article ,Cornified envelope ,03 medical and health sciences ,Cornified Envelope Proline-Rich Proteins ,Psoriasis ,medicine ,Stratum corneum ,Humans ,Life Science ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Cells, Cultured ,integumentary system ,Biopsy, Needle ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Role ,Wild type ,Cell Biology ,medicine.disease ,Immunohistochemistry ,Immunity, Innate ,Anti-Bacterial Agents ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology ,Female ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Function (biology) ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] - Abstract
Contains fulltext : 182646.pdf (Publisher’s version ) (Open Access) Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk.
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- 2017
10. LB1564 Cutaneous Staphylococcus profiling at species level in atopic dermatitis by Single Locus Sequence Typing (SLST) marker design and oligotyping for high-resolution sequencing-based microbial profiling
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Ederveen, T., primary, Smits, J., additional, Hajo, K., additional, Boekhorst, J., additional, van den Bogaard, E., additional, Zeeuwen, P., additional, Schalkwijk, J., additional, and van Hijum, S., additional
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- 2018
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11. 681 Aryl hydrocarbon receptor activation upregulates a battery of antimicrobial genes
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Smits, J., primary, Qu, J., additional, Zeeuwen, P., additional, Schalkwijk, J., additional, Zhou, H., additional, and van den Bogaard, E., additional
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- 2018
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12. 966 The human cutaneous microbiome composition changes after coal tar treatment of both healthy and atopic dermatitis skin
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Smits, J., primary, Ederveen, T., additional, Schalkwijk, J., additional, van Hijum, S., additional, Zeeuwen, P., additional, and van den Bogaard, E., additional
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- 2018
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13. 694 Psoriasis-associated late cornified envelope (LCE) proteins have antibacterial activity
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Niehues, H., primary, Tsoi, L.C., additional, van der Krieken, D., additional, Helder, R., additional, Bouwstra, J., additional, van den Bogaard, E., additional, Elder, J.T., additional, Zeeuwen, P., additional, and Schalkwijk, J., additional
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- 2018
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14. 113 Immortalized N/TERT keratinocytes: An excellent and versatile alternative for primary keratinocytes in experimental dermatological research
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Smits, J., primary, Niehues, H., additional, Rikken, G., additional, van Vlijmen-Willems, I., additional, Zeeuwen, P., additional, Schalkwijk, J., additional, and van den Bogaard, E., additional
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- 2017
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15. 319 The role of TLR-3 in the itch-scratch cycle of nodular prurigo - new insights into innate immune mechanisms of peripheral itch sensitization
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Szollosi, A.G., primary, McDonald, I., additional, Szabó, I.L., additional, Kirby, B., additional, van den Bogaard, E., additional, Schalkwijk, J., additional, and Steinhoff, M., additional
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- 2016
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16. 107 Filaggrin deficiency impacts cutaneous microbiota
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Zeeuwen, P., primary, Ederveen, T., additional, van der Krieken, D., additional, Niehues, H., additional, Boekhorst, J., additional, Kezic, S., additional, Zeeuwen-Franssen, M., additional, van Steensel, M., additional, van Hijum, S., additional, and Schalkwijk, J., additional
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- 2016
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17. 077 Epidermal equivalents of filaggrin null keratinocytes do not show impaired skin barrier function
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Niehues, H., primary, van Vlijmen-Willems, I., additional, Rodijk-Olthuis, D., additional, Schalkwijk, J., additional, van Rossum, M., additional, Wladykowski, E., additional, Brandner, J., additional, van den Bogaard, E., additional, and Zeeuwen, P., additional
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- 2016
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18. Immunohistochemical Localization of SKALP/Elafin in Psoriatic Epidermis
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Schalkwijk, J., primary, van Vlijmen, I.M.J.J., additional, Alkemade, J.A.C., additional, and de Jongh, G.J., additional
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- 1993
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19. LB1564 Cutaneous Staphylococcusprofiling at species level in atopic dermatitis by Single Locus Sequence Typing (SLST) marker design and oligotyping for high-resolution sequencing-based microbial profiling
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Ederveen, T., Smits, J., Hajo, K., Boekhorst, J., van den Bogaard, E., Zeeuwen, P., Schalkwijk, J., and van Hijum, S.
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- 2018
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20. The Aryl Hydrocarbon Receptor Regulates Epidermal Differentiation through Transient Activation of TFAP2A.
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Smits JPH, Qu J, Pardow F, van den Brink NJM, Rodijk-Olthuis D, van Vlijmen-Willems IMJJ, van Heeringen SJ, Zeeuwen PLJM, Schalkwijk J, Zhou H, and van den Bogaard EH
- Abstract
The aryl hydrocarbon receptor (AHR) is an evolutionary conserved environmental sensor identified as an indispensable regulator of epithelial homeostasis and barrier organ function. Molecular signaling cascade and target genes upon AHR activation and their contribution to cell and tissue function are however not fully understood. Multiomics analyses using human skin keratinocytes revealed that upon ligand activation, AHR binds open chromatin to induce expression of transcription factors, for example, TFAP2A, as a swift response to environmental stimuli. The terminal differentiation program, including upregulation of barrier genes, FLG and keratins, was mediated by TFAP2A as a secondary response to AHR activation. The role of AHR-TFAP2A axis in controlling keratinocyte terminal differentiation for proper barrier formation was further confirmed using CRISPR/Cas9 in human epidermal equivalents. Overall, the study provides additional insights into the molecular mechanism behind AHR-mediated barrier function and identifies potential targets for the treatment of skin barrier diseases., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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21. CYSRT1: An Antimicrobial Epidermal Protein that Can Interact with Late Cornified Envelope Proteins.
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Niehues H, Rikken G, Kersten FFJ, Eeftens JM, van Vlijmen-Willems IMJJ, Rodijk-Olthuis D, Jansen PAM, Hendriks WJAJ, Ederveen THA, Schalkwijk J, van den Bogaard EH, and Zeeuwen PLJM
- Subjects
- Cornified Envelope Proline-Rich Proteins genetics, Cornified Envelope Proline-Rich Proteins metabolism, Epidermis metabolism, Keratinocytes metabolism, Proteins metabolism, Skin metabolism, Humans, Anti-Infective Agents metabolism, Psoriasis genetics, Psoriasis metabolism
- Abstract
Late cornified envelope (LCE) proteins are small cationic epidermal proteins with antimicrobial properties, and the combined deletion of LCE3B and LCE3C genes is a risk factor for psoriasis that affects skin microbiome composition. In a yeast two-hybrid screen, we identified CYSRT1 as an interacting partner of members of all LCE groups except LCE6. These interactions were confirmed in a mammalian cell system by coimmunoprecipitation. CYSRT1 is a protein of unknown function that is specifically expressed in cutaneous and oral epithelia and spatially colocalizes with LCE proteins in the upper layers of the suprabasal epidermis. Constitutive CYSRT1 expression is present in fully differentiated epidermis and can be further induced in vivo by disruption of the skin barrier upon stratum corneum removal. Transcriptional regulation correlates to keratinocyte terminal differentiation but not to skin bacteria exposure. Similar to LCEs, CYSRT1 was found to have antibacterial activity against Pseudomonas aeruginosa. Comparative gene sequence analysis and protein amino acid alignment indicate that CYSRT1 is highly conserved among vertebrates and has putative antimicrobial activity. To summarize, we identified CYSRT1 in the outer skin layer, where it colocalizes with LCE proteins and contributes to the constitutive epidermal antimicrobial host defense repertoire., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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22. Investigations into the FLG Null Phenotype: Showcasing the Methodology for CRISPR/Cas9 Editing of Human Keratinocytes.
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Smits JPH, van den Brink NJM, Meesters LD, Hamdaoui H, Niehues H, Jansen PAM, van Vlijmen-Willems IMJJ, Rodijk-Olthuis D, Evrard C, Poumay Y, van Geel M, Hendriks WJAJ, Schalkwijk J, Zeeuwen PLJM, and van den Bogaard EH
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- Humans, Filaggrin Proteins, Keratinocytes metabolism, Phenotype, CRISPR-Cas Systems, Intermediate Filament Proteins metabolism
- Abstract
Ever since the association between FLG loss-of-function variants and ichthyosis vulgaris and atopic dermatitis disease onset was identified, FLGs function has been under investigation. Intraindividual genomic predisposition, immunological confounders, and environmental interactions complicate the comparison between FLG genotypes and related causal effects. Using CRISPR/Cas9, we generated human FLG-knockout (ΔFLG) N/TERT-2G keratinocytes. FLG deficiency was shown by immunohistochemistry of human epidermal equivalent cultures. Next to (partial) loss of structural proteins (involucrin, hornerin, keratin 2, and transglutaminase 1), the stratum corneum was denser and lacked the typical basket weave appearance. In addition, electrical impedance spectroscopy and transepidermal water loss analyses highlighted a compromised epidermal barrier in ΔFLG human epidermal equivalents. Correction of FLG reinstated the presence of keratohyalin granules in the stratum granulosum, FLG protein expression, and expression of the proteins mentioned earlier. The beneficial effects on stratum corneum formation were reflected by the normalization of electrical impedance spectroscopy and transepidermal water loss. This study shows the causal phenotypical and functional consequences of FLG deficiency, indicating that FLG is not only central in epidermal barrier function but also vital for epidermal differentiation by orchestrating the expression of other important epidermal proteins. These observations pave the way to fundamental investigations into the exact role of FLG in skin biology and disease., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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23. Antimicrobial Late Cornified Envelope Proteins: The Psoriasis Risk Factor Deletion of LCE3B/C Genes Affects Microbiota Composition.
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Niehues H, van der Krieken DA, Ederveen THA, Jansen PAM, van Niftrik L, Mesman R, Netea MG, Smits JPH, Schalkwijk J, van den Bogaard EH, and Zeeuwen PLJM
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- Gene Deletion, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Risk Factors, Cornified Envelope Proline-Rich Proteins genetics, Microbiota genetics, Psoriasis genetics
- Abstract
Late cornified envelope proteins are predominantly expressed in the skin and other cornified epithelia. On the basis of sequence similarity, this 18-member homologous gene family has been subdivided into six groups. The LCE3 proteins have been the focus of dermatological research because the combined deletion of LCE3B and LCE3C genes (LCE3B/C-del) is a risk factor for psoriasis. We previously reported that LCE3B/C-del increases the expression of the LCE3A gene and that LCE3 proteins exert antibacterial activity. In this study, we analyzed the antimicrobial properties of other family members and the role of LCE3B/C-del in the modulation of microbiota composition of the skin and oral cavity. Differences in killing efficiency and specificity between the late cornified envelope proteins and their target microbes were found, and the amino acid content rather than the order of the well-conserved central domain of the LCE3A protein was found responsible for its antibacterial activity. In vivo, LCE3B/C-del correlated with a higher beta-diversity in the skin and oral microbiota. From these results, we conclude that all late cornified envelope proteins possess antimicrobial activity. Tissue-specific and genotype-dependent antimicrobial protein profiles impact skin and oral microbiota composition, which could direct toward LCE3B/C-del‒associated dysbiosis and a possible role for microbiota in the pathophysiology of psoriasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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24. Targeting the Cutaneous Microbiota in Atopic Dermatitis by Coal Tar via AHR-Dependent Induction of Antimicrobial Peptides.
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Smits JPH, Ederveen THA, Rikken G, van den Brink NJM, van Vlijmen-Willems IMJJ, Boekhorst J, Kamsteeg M, Schalkwijk J, van Hijum SAFT, Zeeuwen PLJM, and van den Bogaard EH
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- Administration, Cutaneous, Adult, Anti-Infective Agents therapeutic use, Antimicrobial Cationic Peptides immunology, Antimicrobial Cationic Peptides metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Biopsy, Cell Line, Coal Tar therapeutic use, Dermatitis, Atopic immunology, Dermatitis, Atopic microbiology, Dermatitis, Atopic pathology, Dysbiosis immunology, Dysbiosis microbiology, Female, Gene Expression Regulation drug effects, Gene Expression Regulation immunology, Gene Knockdown Techniques, Healthy Volunteers, Humans, Keratinocytes, Male, Microbiota immunology, Middle Aged, Primary Cell Culture, Propionibacterium immunology, Propionibacterium isolation & purification, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Skin drug effects, Skin immunology, Skin pathology, Skin Cream pharmacology, Skin Cream therapeutic use, Staphylococcus aureus immunology, Staphylococcus aureus isolation & purification, Young Adult, Anti-Infective Agents pharmacology, Basic Helix-Loop-Helix Transcription Factors agonists, Coal Tar pharmacology, Dermatitis, Atopic drug therapy, Dysbiosis drug therapy, Microbiota drug effects, Receptors, Aryl Hydrocarbon agonists, Skin microbiology
- Abstract
Skin colonization by Staphylococcus aureus and its relative abundance is associated with atopic dermatitis (AD) disease severity and treatment response. Low levels of antimicrobial peptides in AD skin may be related to the microbial dysbiosis. Therapeutic targeting of the skin microbiome and antimicrobial peptide expression can, therefore, restore skin homeostasis and combat AD. In this study, we analyzed the cutaneous microbiome composition in 7 patients with AD and 10 healthy volunteers upon topical coal tar or vehicle treatment. We implemented and validated a Staphylococcus-specific single-locus sequence typing approach combined with classic 16S ribosomal RNA marker gene sequencing to study the bacterial composition. During coal tar treatment, Staphylococcus abundance decreased, and Propionibacterium abundance increased, suggesting a shift of the microbiota composition toward that of healthy controls. We, furthermore, identified a hitherto unknown therapeutic mode of action of coal tar, namely the induction of keratinocyte-derived antimicrobial peptides via activation of the aryl hydrocarbon receptor. Restoring antimicrobial peptide levels in AD skin via aryl hydrocarbon receptor-dependent transcription regulation can be beneficial by creating a (anti)microbial milieu that is less prone to infection and inflammation. This underscores the importance of coal tar in the therapeutic aryl hydrocarbon receptor armamentarium and highlights the aryl hydrocarbon receptor as a target for drug development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2020
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25. Reply to Meisel et al.
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Zeeuwen PLJM, Boekhorst J, Ederveen THA, Kleerebezem M, Schalkwijk J, van Hijum SAFT, and Timmerman HM
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- 2017
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26. Spread of Psoriasiform Inflammation to Remote Tissues Is Restricted by the Atypical Chemokine Receptor ACKR2.
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Shams K, Wilson GJ, Singh M, van den Bogaard EH, Le Brocq ML, Holmes S, Schalkwijk J, Burden AD, McKimmie CS, and Graham GJ
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- Animals, Biopsy, Needle, Cells, Cultured, Disease Models, Animal, Gene Expression Regulation, Humans, Imiquimod, Immunohistochemistry, Inflammation pathology, Keratinocytes cytology, Keratinocytes drug effects, Mice, Mice, Inbred C57BL, Phenotype, Polymerase Chain Reaction methods, Psoriasis drug therapy, Random Allocation, Receptors, Chemokine metabolism, Reference Values, Statistics, Nonparametric, Up-Regulation, Aminoquinolines pharmacology, Inflammation drug therapy, Inflammation genetics, Psoriasis genetics, Psoriasis pathology, Receptors, Chemokine genetics
- Abstract
Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis-associated atypical chemokine receptor 2 (ACKR2) binds, internalizes and degrades most proinflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion. Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays, and the imiquimod-induced model of psoriasiform skin inflammation. Localized inflammation and IFN-γ together up-regulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2017
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27. Cell Surface Expression of HLA-Cw6 by Human Epidermal Keratinocytes: Positive Regulation by Cytokines, Lack of Correlation to a Variant Upstream of HLA-C.
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van den Bogaard EH, Tijssen HJ, Rodijk-Olthuis D, van Houwelingen KP, Coenen MJ, Marget M, Schalkwijk J, and Joosten I
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- 3' Untranslated Regions genetics, Antigen Presentation genetics, Antigen Presentation immunology, Autoantigens genetics, Autoantigens immunology, Autoantigens metabolism, Epidermal Cells, HLA-C Antigens genetics, HLA-C Antigens immunology, Healthy Volunteers, Humans, MicroRNAs metabolism, Polymorphism, Single Nucleotide, Primary Cell Culture, Psoriasis genetics, Psoriasis immunology, Psoriasis pathology, Risk Factors, Up-Regulation, Cytokines metabolism, Epidermis metabolism, HLA-C Antigens metabolism, Keratinocytes metabolism
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- 2016
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28. Genetic and pharmacological analysis identifies a physiological role for the AHR in epidermal differentiation.
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van den Bogaard EH, Podolsky MA, Smits JP, Cui X, John C, Gowda K, Desai D, Amin SG, Schalkwijk J, Perdew GH, and Glick AB
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- Allyl Compounds pharmacology, Animals, Azo Compounds pharmacology, Cell Adhesion drug effects, Cell Adhesion physiology, Cell Differentiation drug effects, Cells, Cultured, Epidermis drug effects, Epidermis physiology, Humans, Indazoles pharmacology, Indoles pharmacology, Keratinocytes drug effects, Keratinocytes physiology, Mice, Mice, Knockout, Models, Animal, Purines pharmacology, Pyrazoles pharmacology, Receptors, Aryl Hydrocarbon drug effects, Signal Transduction drug effects, Signal Transduction physiology, Cell Differentiation physiology, Epidermal Cells, Keratinocytes cytology, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon physiology
- Abstract
Stimulation of the aryl hydrocarbon receptor (AHR) by xenobiotics is known to affect epidermal differentiation and skin barrier formation. The physiological role of endogenous AHR signaling in keratinocyte differentiation is not known. We used murine and human skin models to address the hypothesis that AHR activation is required for normal keratinocyte differentiation. Using transcriptome analysis of Ahr(-/-) and Ahr(+/+) murine keratinocytes, we found significant enrichment of differentially expressed genes linked to epidermal differentiation. Primary Ahr(-/-) keratinocytes showed a significant reduction in terminal differentiation gene and protein expression, similar to Ahr(+/+) keratinocytes treated with AHR antagonists GNF351 and CH223191, or the selective AHR modulator (SAhRM) SGA360. In vitro keratinocyte differentiation led to increased AHR levels and subsequent nuclear translocation, followed by induced CYP1A1 gene expression. Monolayer cultured primary human keratinocytes treated with AHR antagonists also showed an impaired terminal differentiation program. Inactivation of AHR activity during human skin equivalent development severely impaired epidermal stratification, terminal differentiation protein expression, and stratum corneum formation. As disturbed epidermal differentiation is a main feature of many skin diseases, pharmacological agents targeting AHR signaling or future identification of endogenous keratinocyte-derived AHR ligands should be considered as potential new drugs in dermatology.
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- 2015
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29. Crosstalk between keratinocytes and T cells in a 3D microenvironment: a model to study inflammatory skin diseases.
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van den Bogaard EH, Tjabringa GS, Joosten I, Vonk-Bergers M, van Rijssen E, Tijssen HJ, Erkens M, Schalkwijk J, and Koenen HJPM
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- Anti-Inflammatory Agents pharmacology, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes metabolism, Cell Communication drug effects, Cell Culture Techniques methods, Cell Movement drug effects, Cell Movement immunology, Dermatitis, Atopic metabolism, Dermatitis, Atopic pathology, Dermis cytology, Dermis immunology, Dermis metabolism, Filaggrin Proteins, Humans, Keratinocytes cytology, Keratinocytes metabolism, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Primary Cell Culture, Psoriasis metabolism, Psoriasis pathology, Th1 Cells cytology, Th1 Cells immunology, Th1 Cells metabolism, Th17 Cells cytology, Th17 Cells immunology, Th17 Cells metabolism, CD4-Positive T-Lymphocytes immunology, Cell Communication immunology, Dermatitis, Atopic immunology, Keratinocytes immunology, Psoriasis immunology, Receptor Cross-Talk immunology
- Abstract
The interaction between keratinocytes and immune cells plays a major role in the development of inflammatory skin diseases like psoriasis and atopic dermatitis. Pharmacological intervention to inhibit T cell-derived proinflammatory mediators is an effective therapy in the treatment of psoriasis. Here, we present a model to study the interaction between keratinocytes and T cells in a three-dimensional (3D) microenvironment, based on human skin equivalents populated with CD4+ T cells. T cell migration into the dermis initiated keratinocyte activation within 2 days, with hallmarks of a psoriasiform inflammation after 4 days. Expression of epidermal psoriasis marker genes was upregulated, and proinflammatory cytokines and chemokines were highly expressed. Disturbed epidermal differentiation was shown by downregulated filaggrin expression and involucrin expression in the spinous layer. These effects were mediated via soluble factors produced by the T cells. The psoriasiform inflammation was also observed using T helper type 1 (Th1)- and Th17-polarized CD4+ T cells. We validated our model by treatment with anti-inflammatory drugs that reduced the expression of proinflammatory cytokines and chemokines and suppressed the psoriasiform inflammation. We propose that our T cell-driven inflammatory skin equivalent model has potential to study the pathogenesis of inflammatory skin diseases and may serve as a preclinical screening tool for anti-inflammatory drugs.
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- 2014
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30. Association of β-defensin copy number and psoriasis in three cohorts of European origin.
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Stuart PE, Hüffmeier U, Nair RP, Palla R, Tejasvi T, Schalkwijk J, Elder JT, Reis A, and Armour JAL
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- Adult, Aged, Case-Control Studies, Cohort Studies, Data Interpretation, Statistical, Europe, Female, Genetic Association Studies, Germany epidemiology, Humans, Male, Michigan epidemiology, Middle Aged, Netherlands epidemiology, Psoriasis epidemiology, DNA genetics, Gene Dosage genetics, Psoriasis ethnology, Psoriasis genetics, beta-Defensins genetics
- Abstract
A single previous study has demonstrated significant association of psoriasis with copy number of β-defensin genes, using DNA from psoriasis cases and controls from Nijmegen and Erlangen. In this study, we attempted to replicate that finding in larger new cohorts from Erlangen (N=2,017) and Michigan (N=5,412), using improved methods for β-defensin copy number determination based on the paralog ratio test, and enhanced methods of analysis and association testing implemented in the CNVtools resource. We demonstrate that the association with psoriasis found in the discovery sample is maintained after applying improved typing and analysis methods (P=5.5 × 10(-4), odds ratio (OR)=1.25). We also find that the association is replicated in 2,616 cases and 2,526 controls from Michigan, although at reduced significance (P=0.014), but not in new samples from Erlangen (1,396 cases and 621 controls, P=0.38). Meta-analysis across all cohorts suggests a nominally significant association (P=6.6 × 10(-3)/2 × 10(-4)) with an effect size (OR=1.081) much lower than found in the discovery study (OR=1.32). This reduced effect size and significance on replication is consistent with a genuine but weak association.
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- 2012
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31. Genetics of psoriasis: evidence for epistatic interaction between skin barrier abnormalities and immune deviation.
- Author
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Bergboer JGM, Zeeuwen PLJM, and Schalkwijk J
- Subjects
- Autoimmune Diseases genetics, Autoimmune Diseases immunology, Autoimmune Diseases physiopathology, Epidermis immunology, Epistasis, Genetic, Filaggrin Proteins, Humans, Models, Biological, Polymorphism, Genetic, Psoriasis physiopathology, Risk Factors, beta-Defensins genetics, beta-Defensins immunology, Epidermis physiopathology, Psoriasis genetics, Psoriasis immunology
- Abstract
Psoriasis was until recently regarded as a T-cell-driven disease with presumed (auto)immune mechanisms as its primary cause. This view was supported by clinical data and genetic studies that identified risk factors functioning in adaptive and innate immunity, such as HLA-C*06, ERAP1, the IL-23 pathway, and NF-k B signaling. Candidate gene approaches and genome-wide association studies, however, have identified copy number polymorphisms of the b-defensin cluster and deletion of late cornified envelope (LCE) 3B and 3C genes (LCE3C_LCE3B-del) as psoriasis risk factors.As these genes are expressed in epithelial cells and not by the immune system, these findings may cause a change of paradigm for psoriasis, not unlike the reported filaggrin association that has profoundly changed the views on atopic dermatitis. In addition to genetic polymorphisms of the immune system, genetic variations affecting the skin barrier are likely to contribute to psoriasis. Recent studies have shown epistatic interactions involving HLA-C*06, ERAP1, and LCE3C_LCE3B-del, which makes psoriasis a unique model to investigate genetic and biological interactions of associated genes in a complex disease. We present a model for disease initiation and perpetuation, which integrates the available genetic, immunobiological, and clinical data.
- Published
- 2012
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32. Koebner phenomenon in psoriasis is not associated with deletion of late cornified envelope genes LCE3B and LCE3C.
- Author
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Bergboer JG, Oostveen AM, de Jager ME, Zeeuwen PL, Joosten I, Seyger MM, and Schalkwijk J
- Subjects
- Gene Deletion, Humans, Psoriasis pathology, Cornified Envelope Proline-Rich Proteins genetics, Psoriasis genetics, Skin pathology
- Published
- 2012
- Full Text
- View/download PDF
33. Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
- Author
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Riveira-Munoz E, He SM, Escaramís G, Stuart PE, Hüffmeier U, Lee C, Kirby B, Oka A, Giardina E, Liao W, Bergboer J, Kainu K, de Cid R, Munkhbat B, Zeeuwen PL, Armour JA, Poon A, Mabuchi T, Ozawa A, Zawirska A, Burden AD, Barker JN, Capon F, Traupe H, Sun LD, Cui Y, Yin XY, Chen G, Lim HW, Nair RP, Voorhees JJ, Tejasvi T, Pujol R, Munkhtuvshin N, Fischer J, Kere J, Schalkwijk J, Bowcock A, Kwok PY, Novelli G, Inoko H, Ryan AW, Trembath RC, Reis A, Zhang XJ, Elder JT, and Estivill X
- Subjects
- Adolescent, Adult, Asian People genetics, Epistasis, Genetic, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Young Adult, Cornified Envelope Proline-Rich Proteins genetics, Gene Deletion, HLA-C Antigens genetics, Psoriasis genetics
- Abstract
A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.15-1.27)), and for the first time directly demonstrates the deletion's association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.
- Published
- 2011
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34. Epidermal expression of host response genes upon skin barrier disruption in normal skin and uninvolved skin of psoriasis and atopic dermatitis patients.
- Author
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de Koning HD, Kamsteeg M, Rodijk-Olthuis D, van Vlijmen-Willems IM, van Erp PE, Schalkwijk J, and Zeeuwen PL
- Subjects
- Antimicrobial Cationic Peptides metabolism, Epidermis metabolism, Epidermis physiopathology, Humans, Permeability, Psoriasis genetics, Psoriasis physiopathology, Antimicrobial Cationic Peptides genetics, Dermatitis, Atopic genetics, Dermatitis, Atopic metabolism, Dermatitis, Atopic physiopathology, Psoriasis metabolism
- Published
- 2011
- Full Text
- View/download PDF
35. A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis.
- Author
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de Koning HD, Rodijk-Olthuis D, van Vlijmen-Willems IM, Joosten LA, Netea MG, Schalkwijk J, and Zeeuwen PL
- Subjects
- Antigens, Fungal immunology, Candida albicans immunology, Cells, Cultured, Dermatitis, Atopic pathology, Epidermal Cells, Gene Expression drug effects, Gene Expression immunology, Humans, Interferons pharmacology, Interleukin-17 pharmacology, Interleukins pharmacology, Keratinocytes cytology, Keratinocytes immunology, Lectins, C-Type, Ligands, Membrane Proteins immunology, Membrane Proteins metabolism, Nerve Tissue Proteins immunology, Nerve Tissue Proteins metabolism, Psoriasis pathology, RNA, Messenger metabolism, Up-Regulation immunology, beta-Glucans immunology, beta-Glucans metabolism, Interleukin-22, Dermatitis, Atopic immunology, Epidermis immunology, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Psoriasis immunology
- Abstract
Human epidermis plays an important role in host defense by acting as a physical barrier and signaling interface between the environment and the immune system. Pattern recognition receptors (PRRs) are crucial to maintain homeostasis and provide protection during infection, but are also causally involved in monogenic auto-inflammatory diseases. This study aimed to investigate the epidermal expression of PRRs and several associated host defense molecules in healthy human skin, psoriasis, and atopic dermatitis (AD). Using microarray analysis and real-time quantitative PCR, we found that many of these genes are transcribed in normal human epidermis. Only a few genes were differentially induced in psoriasis (CLEC7A (dectin-1), Toll-like receptor (TLR) 4, and mannose receptor C type 1 (MRC1)) or AD (MRC1, IL1RN, and IL1β) compared with normal epidermis. A remarkably high expression of dectin-1 mRNA was observed in psoriatic epidermis and this was corroborated by immunohistochemistry. In cultured primary human keratinocytes, dectin-1 expression was induced by IFN-γ, IFN-α, and Th17 cytokines. Keratinocytes were unresponsive, however, to dectin-1 ligands such as β-glucan or heat-killed Candida albicans, nor did we observe synergy with TLR2/TLR5 ligands. In conclusion, upregulation of dectin-1 in psoriatic lesions seems to be under control of psoriasis-associated cytokines. Its role in the biology of skin inflammation and infection remains to be explored.
- Published
- 2010
- Full Text
- View/download PDF
36. Deletion of Late Cornified Envelope 3B and 3C genes is not associated with atopic dermatitis.
- Author
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Bergboer JG, Zeeuwen PL, Irvine AD, Weidinger S, Giardina E, Novelli G, Den Heijer M, Rodriguez E, Illig T, Riveira-Munoz E, Campbell LE, Tyson J, Dannhauser EN, O'Regan GM, Galli E, Klopp N, Koppelman GH, Novak N, Estivill X, McLean WH, Postma DS, Armour JA, and Schalkwijk J
- Subjects
- Adult, Aged, Asthma ethnology, Asthma genetics, Case-Control Studies, Cohort Studies, Europe epidemiology, Female, Filaggrin Proteins, Gene Deletion, Gene Frequency, Genotype, Humans, Immunoglobulin E blood, Linkage Disequilibrium, Male, Middle Aged, Cornified Envelope Proline-Rich Proteins genetics, Dermatitis, Atopic ethnology, Dermatitis, Atopic genetics, White People genetics
- Abstract
Atopic dermatitis (AD) and psoriasis are common skin diseases characterized by cutaneous inflammation and disturbed epidermal differentiation. Genome-wide analyses have shown overlapping susceptibility loci, such as the epidermal differentiation complex on chromosome 1q21. Recently, a deletion on 1q21 (LCE3C_LCE3B-del), comprising LCE3B and LCE3C, two members of the late cornified envelope (LCE) gene cluster, was found to be associated with psoriasis. Although the mechanistic role of LCE proteins in psoriasis has not been identified, these proteins are putatively involved in skin barrier formation and repair. Considering the potential genetic overlap between the two diseases and the recent finding that mutations in the skin barrier protein filaggrin are associated with AD, we investigated a possible association between LCE3C_LCE3B-del and AD. Evaluation of four different cohorts of European ancestry, containing a total of 1075 AD patients and 1658 controls, did not provide evidence for such an association. Subgroup analysis did not reveal an association with concomitant asthma. Our data suggest that the potential roles of skin barrier defects in the pathogenesis of AD and psoriasis are based on distinct genetic causes.
- Published
- 2010
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37. Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors.
- Author
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Hüffmeier U, Bergboer JG, Becker T, Armour JA, Traupe H, Estivill X, Riveira-Munoz E, Mössner R, Reich K, Kurrat W, Wienker TF, Schalkwijk J, Zeeuwen PL, and Reis A
- Subjects
- Adult, Age of Onset, Gene Deletion, Gene Dosage, Gene Frequency, Genetic Predisposition to Disease epidemiology, Germany epidemiology, Haplotypes, Humans, Polymorphism, Single Nucleotide, Proteins genetics, Risk Factors, beta-Defensins genetics, Cornified Envelope Proline-Rich Proteins genetics, Psoriasis epidemiology, Psoriasis genetics, White People statistics & numerical data
- Abstract
Recently, a deletion of two late cornified envelope (LCE) genes within the epidermal differentiation complex on chromosome 1 was shown to be overrepresented in 1,426 psoriasis vulgaris (PsV) patients of European ancestry. In this study, we report a confirmation of this finding in 1,354 PsV patients and 937 control individuals of German origin. We found an allele frequency of the deletion of 70.9% in PsV patients and of 64.9% in control individuals (chi(2)=17.44, P=2.97 x 10(-5), odds ratio (95% confidence interval)=1.31 (1.15-1.48)). The overall copy number of the two LCE genes had no influence on the age of onset, but we observed a dosage effect at the genotype level. There was no evidence of statistically significant interaction with copy number of the beta-defensin cluster on 8p23.1 or with an IL-23R pathway variant in a combined data set of German and Dutch individuals, whereas evidence for interaction with the PSORS1 risk allele in German individuals was marginal and did not remain significant after correction for multiple testing. Our study confirms the recently published finding that the deletion of the two LCE genes is a susceptibility factor for PsV with dosage effect, while, because of power limitation, no final conclusion regarding interaction with other PsV risk factors can be made at this stage.
- Published
- 2010
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38. Expression of the vanin gene family in normal and inflamed human skin: induction by proinflammatory cytokines.
- Author
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Jansen PA, Kamsteeg M, Rodijk-Olthuis D, van Vlijmen-Willems IM, de Jongh GJ, Bergers M, Tjabringa GS, Zeeuwen PL, and Schalkwijk J
- Subjects
- Caspase Inhibitors, Cell Adhesion Molecules analysis, Cysteamine pharmacology, GPI-Linked Proteins, Gene Expression Regulation drug effects, Humans, Hydrolases analysis, Keratinocytes metabolism, PPAR gamma physiology, RNA, Messenger analysis, Skin metabolism, Transglutaminases antagonists & inhibitors, Amidohydrolases genetics, Cell Adhesion Molecules genetics, Cytokines pharmacology, Hydrolases genetics, Psoriasis metabolism
- Abstract
The vanin gene family encodes secreted and membrane-bound ectoenzymes that convert pantetheine into pantothenic acid and cysteamine. Recent studies in a mouse colitis model indicated that vanin-1 has proinflammatory activity and suggest that pantetheinases are potential therapeutic targets in inflammatory diseases. In a microarray analysis of epidermal gene expression of psoriasis and atopic dermatitis lesions, we identified vanin-3 as the gene showing the highest differential expression of all annotated genes that we studied (19-fold upregulation in psoriasis). Quantitative real-time PCR analysis confirmed the microarray data on vanin-3 and showed similar induction of vanin-1, but not of vanin-2, in psoriatic epidermis. Immunohistochemistry showed that vanin-3 is expressed in the differentiated epidermal layers. Using submerged and organotypic keratinocyte cultures, we found that vanin-1 and vanin-3 are induced at the mRNA and protein level by psoriasis-associated proinflammatory cytokines (Th17/Th1) but not by Th2 cytokines. We hypothesize that increased levels of pantetheinase activity are part of the inflammatory-regenerative epidermal differentiation program, and may contribute to the phenotype observed in psoriasis.
- Published
- 2009
- Full Text
- View/download PDF
39. Effect of daily stressors on psoriasis: a prospective study.
- Author
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Verhoeven EW, Kraaimaat FW, Jong EM, Schalkwijk J, van de Kerkhof PC, and Evers AW
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Prospective Studies, Severity of Illness Index, Psoriasis etiology, Stress, Psychological complications
- Published
- 2009
- Full Text
- View/download PDF
40. The biology of cystatin M/E and its cognate target proteases.
- Author
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Zeeuwen PL, Cheng T, and Schalkwijk J
- Subjects
- Animals, Cysteine Endopeptidases metabolism, Disease Models, Animal, Epidermis metabolism, Genes, Tumor Suppressor, Hair Follicle metabolism, Humans, Ichthyosis genetics, Inflammation, Lysosomes metabolism, Mice, Models, Biological, Cystatin M physiology, Peptide Hydrolases metabolism
- Abstract
Cystatin M/E is a member of a superfamily of evolutionarily-related cysteine protease inhibitors that provide regulatory and protective functions against uncontrolled proteolysis by cysteine proteases. Although most cystatins are ubiquitously expressed, high levels of cystatin M/E expression are mainly restricted to the epithelia of the skin (epidermis, hair follicles, sebaceous glands, and sweat glands) and to a few extracutaneous tissues. The identification of its physiological targets and the localization of these proteases in skin have suggested a regulatory role for cystatin M/E in epidermal differentiation. In vitro biochemical approaches as well as the use of in vivo mouse models have revealed that cystatin M/E is a key molecule in a biochemical pathway that controls skin barrier formation by the regulation of both crosslinking and desquamation of the stratum corneum. Cystatin M/E directly controls the activity of cathepsin V, cathepsin L, and legumain, thereby regulating the processing of transglutaminases. Misregulation of this pathway by unrestrained protease activity, as seen in cystatin M/E-deficient mice, leads to abnormal stratum corneum and hair follicle formation, as well as to severe disturbance of skin barrier function. Here, we review the current knowledge on cystatin M/E in skin barrier formation and its potential role as a tumor suppressor gene.
- Published
- 2009
- Full Text
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41. Colocalization of cystatin M/E and its target proteases suggests a role in terminal differentiation of human hair follicle and nail.
- Author
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Cheng T, van Vlijmen-Willems IM, Hitomi K, Pasch MC, van Erp PE, Schalkwijk J, and Zeeuwen PL
- Subjects
- Cathepsin L, Hair Follicle cytology, Humans, Membrane Proteins metabolism, Nails cytology, Protein Precursors metabolism, Signal Transduction physiology, Cathepsins metabolism, Cell Differentiation physiology, Cystatin M metabolism, Cysteine Endopeptidases metabolism, Hair Follicle metabolism, Nails metabolism, Transglutaminases metabolism
- Abstract
The cysteine protease inhibitor cystatin M/E is a key regulator of a biochemical pathway that leads to epidermal terminal differentiation by inhibition of its target proteases cathepsin L, cathepsin V, and legumain. Inhibition of cathepsin L is important in the cornification process of the skin, as we have recently demonstrated that cathepsin L is the elusive processing and activating protease for transglutaminase 3, an enzyme that is responsible for crosslinking of structural proteins in cornified envelope formation. Here, we study the localization of all players of this pathway in the human hair follicle and nail unit in order to elucidate their possible role in the biology of these epidermal appendages. We found that cathepsin L and transglutaminase 3 specifically colocalize in the hair bulb and the nail matrix, the regions that provide cells that terminally differentiate to the hair fiber and the nail plate, respectively. Furthermore, transglutaminase 3 also colocalizes with the structural proteins loricrin and involucrin, which are established transglutaminase substrates. These findings suggest that cathepsin L and transglutaminase 3 could be involved in the pathway that leads to terminal differentiation, not only in the epidermis but also in the human hair follicle and nail unit.
- Published
- 2009
- Full Text
- View/download PDF
42. Increased expression of carbonic anhydrase II (CA II) in lesional skin of atopic dermatitis: regulation by Th2 cytokines.
- Author
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Kamsteeg M, Zeeuwen PL, de Jongh GJ, Rodijk-Olthuis D, Zeeuwen-Franssen ME, van Erp PE, and Schalkwijk J
- Subjects
- Biopsy, Carbonic Anhydrase II genetics, Case-Control Studies, Dermatitis, Atopic genetics, Dermatitis, Atopic pathology, Humans, Middle Aged, Oligonucleotide Array Sequence Analysis, Psoriasis genetics, Psoriasis metabolism, Psoriasis pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Skin pathology, Carbonic Anhydrase II metabolism, Cytokines physiology, Dermatitis, Atopic metabolism, Gene Expression Regulation, Enzymologic physiology, Skin metabolism, Th2 Cells physiology
- Published
- 2007
- Full Text
- View/download PDF
43. Cross-linking of elafin/SKALP to elastic fibers in photodamaged skin: too much of a good thing?
- Author
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Schalkwijk J
- Subjects
- Elasticity, Humans, Cross-Linking Reagents metabolism, Elafin metabolism, Skin Aging pathology, Skin Diseases metabolism, Skin Diseases pathology
- Abstract
Muto et al. report that UVA light induces the expression of elafin, a potent elastase inhibitor, in skin fibroblasts. Elafin binds to elastic fibers by transglutaminase-mediated cross-linking and protects against proteolytic breakdown. Decreased degradation could contribute to accumulation of elastotic material in photodamaged skin. Elastase and its locally produced inhibitors play a role in actinic elastosis.
- Published
- 2007
- Full Text
- View/download PDF
44. Colocalization of cystatin M/E and cathepsin V in lamellar granules and corneodesmosomes suggests a functional role in epidermal differentiation.
- Author
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Zeeuwen PL, Ishida-Yamamoto A, van Vlijmen-Willems IM, Cheng T, Bergers M, Iizuka H, and Schalkwijk J
- Subjects
- Cathepsins physiology, Cell Differentiation, Cystatin M, Cystatins physiology, Cysteine Endopeptidases physiology, Epidermis chemistry, Hair Follicle chemistry, Humans, Microscopy, Fluorescence, Cathepsins analysis, Cystatins analysis, Cysteine Endopeptidases analysis, Cytoplasmic Granules chemistry, Desmosomes chemistry, Epidermis ultrastructure
- Abstract
Cystatin M/E is a cysteine protease inhibitor with two distinct binding sites for papain-like cysteine proteases (family C1) and the asparaginyl endopeptidase (AEP) legumain of family C13. We have previously demonstrated that deficiency of cystatin M/E in mice causes ichthyosiform skin changes and barrier disruption, which could be caused by unrestrained AEP activity. Recently, we provided biochemical evidence that human cathepsin V (CTSV) and cathepsin L (CTSL) are additional biological targets for human cystatin M/E. To address the possible role of these three proteases and their inhibitor in epidermal differentiation, we investigated the localization of these proteins in normal human skin. Whereas CTSL and AEP were broadly expressed in epithelial cells of the skin, we found a specific colocalization of cystatin M/E and CTSV in the stratum granulosum and in the root sheets of the hair follicle, using immunofluorescence microscopy. Immunoelectron microscopy revealed that cystatin M/E and CTSV are separately transported within the lamellar granules. Cystatin M/E was also found in the extracellular space in the stratum corneum associated with corneodesmosomes, where it was closely associated with CTSV. Based on the striking stratum-specific colocalization of cystatin M/E and CTSV, we propose that these molecules could have an important role in epidermal differentiation and desquamation.
- Published
- 2007
- Full Text
- View/download PDF
45. High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis.
- Author
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de Jongh GJ, Zeeuwen PL, Kucharekova M, Pfundt R, van der Valk PG, Blokx W, Dogan A, Hiemstra PS, van de Kerkhof PC, and Schalkwijk J
- Subjects
- Anti-Infective Agents, Biopsy, Cell Differentiation, Cell Division, Dermatitis, Atopic pathology, Humans, Immunohistochemistry, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Psoriasis pathology, Defensins genetics, Dermatitis, Atopic genetics, Keratinocytes physiology, Psoriasis genetics
- Abstract
Recently, it was shown that lesional skin of atopic dermatitis patients expresses low levels of some antimicrobial peptides, compared with psoriasis patients. Here we performed microarray analysis on mRNA from purified lesional epidermal cells of patients with chronic plaque psoriasis and chronic atopic dermatitis, to investigate whether this is a general phenomenon for host defense proteins, and how specific it is for this class of molecules. Microarray data were confirmed on a selected set of genes by quantitative PCR and at the protein level by immunohistochemistry. We found overexpression of many antimicrobial proteins in keratinocytes from psoriatic skin compared with atopic dermatitis skin. Interestingly, we observed that markers of normal differentiation and the activated/hyperproliferative epidermal phenotype were expressed at equal levels. Chronic lesions of psoriasis and atopic dermatitis patients are remarkably similar with respect to cellular proliferation. We conclude that psoriatic epidermis expresses high levels of host defense proteins compared with atopic dermatitis epidermis, and this phenomenon appears to be specific for these proteins. It remains to be investigated whether this is caused by genetic polymorphisms in pathways leading to an epidermal antimicrobial response, or by differences in the cellular infiltrate in psoriasis compared with atopic dermatitis.
- Published
- 2005
- Full Text
- View/download PDF
46. Phenotypical and functional differences in germinative subpopulations derived from normal and psoriatic epidermis.
- Author
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Franssen ME, Zeeuwen PL, Vierwinden G, van de Kerkhof PC, Schalkwijk J, and van Erp PE
- Subjects
- Biomarkers, Biopsy, Cell Division physiology, Cells, Cultured, Flow Cytometry, Humans, Integrin beta1 genetics, Keratinocytes physiology, Ki-67 Antigen genetics, Phenotype, Polymerase Chain Reaction, RNA, Messenger analysis, Epidermis pathology, Keratinocytes pathology, Psoriasis pathology
- Abstract
A model that explains how maintenance of normal homeostasis in human epidermis is achieved describes a heterogeneous cell population of stem cells (SC) and transit amplifying cells (TAC). There must be a tightly regulated balance between SC self-renewal and the generation of TAC that undergo a limited number of divisions before giving rise to postmitotic, terminally differentiated cells. To investigate whether this balance is disturbed in psoriatic epidermis, we have characterized flow sorted enriched SC and TAC using immunocytochemistry, flow cytometry, and real-time quantitative PCR. Our data demonstrate phenotypical and functional differences in SC (beta(1)-integrin bright) and TAC (beta(1)-integrin dim) enriched fractions between normal and psoriatic keratinocytes. Some of these were expected, such as mRNA levels of keratins 6 and 10 and of the Ki-67 antigen. Most remarkable were differences in phenotype of the psoriatic TAC compared with TAC from normal skin. These subpopulations also displayed striking differences following culture. Downregulation of markers associated with the regenerative phenotype (psoriasin, elafin, psoriasis-associated fatty acid binding protein) in cultured psoriatic dim cells in the absence of hyperproliferation suggests that proliferation and regenerative maturation are coupled. From these results, in combination with our earlier findings, we propose a model for epidermal growth control in which TAC play a crucial role.
- Published
- 2005
- Full Text
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47. Deficiency of tenascin-X causes abnormalities in dermal elastic fiber morphology.
- Author
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Zweers MC, van Vlijmen-Willems IM, van Kuppevelt TH, Mecham RP, Steijlen PM, Bristow J, and Schalkwijk J
- Subjects
- Adult, Case-Control Studies, Cells, Cultured, Collagen metabolism, Dermis metabolism, Dermis ultrastructure, Elastic Tissue ultrastructure, Fibrillins, Fibroblasts metabolism, Fibroblasts ultrastructure, Humans, Immunohistochemistry, Metabolism, Inborn Errors metabolism, Metabolism, Inborn Errors pathology, Microfibrils ultrastructure, Microfilament Proteins metabolism, Microscopy, Electron, Middle Aged, Dermis pathology, Ehlers-Danlos Syndrome metabolism, Ehlers-Danlos Syndrome pathology, Elastic Tissue pathology, Tenascin deficiency
- Abstract
Deficiency of the extracellular matrix protein tenascin-X (TNX) was recently described as the molecular basis of a new, recessive type of Ehlers-Danlos syndrome. Here we report gross abnormalities of the elastic fibers and microfibrils in the dermis of these patients, and reduced dermal collagen content, as determined by quantitative image analysis. The ascending, fine elastic fibers in the papillary dermis were absent or inconspicuous and had few branches. The coarse elastic fibers of the reticular dermis were fragmented and clumped. At the ultrastructural level, irregular and immature elastin fibers and fibers devoid of microfibrils were observed. In TNX-deficient patients the dermal collagen density was reduced, but no structural abnormalities in the collagen fibrils were found. These findings suggest that both elastic fiber abnormalities and reduced collagen content contribute to the observed phenotype in TNX-deficient patients.
- Published
- 2004
- Full Text
- View/download PDF
48. Human single-chain antibodies reactive with native chondroitin sulfate detect chondroitin sulfate alterations in melanoma and psoriasis.
- Author
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Smetsers TF, van de Westerlo EM, ten Dam GB, Overes IM, Schalkwijk J, van Muijen GN, and van Kuppevelt TH
- Subjects
- Chondroitin Sulfates analysis, Chondroitin Sulfates chemistry, Epitopes, Humans, Melanoma secondary, Sensitivity and Specificity, Skin chemistry, Antibodies immunology, Chondroitin Sulfates immunology, Melanoma chemistry, Psoriasis metabolism
- Abstract
Chondroitin sulfate (CS) belongs to the group of glycosaminoglycans (GAGs), which are linear polysaccharides, located in the extracellular matrix and on the cell surface. To study the structure and distribution of CS in human skin and skin disorders, we have selected antibodies using phage display technique against CS. Four unique human anti-CS single-chain antibodies were selected: IO3D9, IO3H10, IO3H12, and IO4C2. We determined their amino acid sequence and evaluated their CS reactivity using ELISA and immunohistochemistry. Antibodies were reactive with CS, but not with other GAGs except for IO4C2, which was also reactive with heparin. Antibody IO3D9 showed a strong reactivity with highly sulfated CS (CSE). All antibodies displayed a different staining pattern in rat kidney, indicating the recognition of unique CS epitopes. In normal skin, the papillary dermis but not the reticular dermis was strongly stained. Antibody IO3H12 also stained basal keratinocytes. We applied these antibodies to study CS expression and localization in melanoma and psoriasis. A strong immunoreactivity with the extracellular matrix of melanoma metastases could be observed for all four antibodies, while in atypical nevi a less extensive reactivity with only the papillary dermis was observed. In psoriatic lesions, CS could be observed in the papillary dermis and in the reticular dermis, whereas the specific location in the papillary dermis found in normal skin was completely lost. In conclusion, human phage-display-derived anti-CS antibodies have been selected, characterized, and applied to detect CS alterations in skin conditions. Altered CS composition was detected in melanoma and psoriasis.
- Published
- 2004
- Full Text
- View/download PDF
49. Tumor necrosis factor related apoptosis inducing ligand triggers apoptosis in dividing but not in differentiating human epidermal keratinocytes.
- Author
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Jansen BJ, van Ruissen F, Cerneus S, Cloin W, Bergers M, van Erp PE, and Schalkwijk J
- Subjects
- Apoptosis Regulatory Proteins, Caspase 3, Caspase 8, Caspase 9, Caspases metabolism, Cell Differentiation drug effects, Cell Differentiation physiology, Cells, Cultured, DNA Fragmentation drug effects, Deoxyribonucleases genetics, Gene Expression, Humans, Ligands, Membrane Glycoproteins genetics, Poly-ADP-Ribose Binding Proteins, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha genetics, Antineoplastic Agents pharmacology, DNA Fragmentation physiology, Epidermal Cells, Keratinocytes cytology, Keratinocytes physiology, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Using serial analysis of gene expression we have previously identified the expression of several pro-apoptotic and anti-apoptotic genes in cultured human primary epidermal keratinocytes, including tumor necrosis factor related apoptosis inducing ligand (TRAIL). TRAIL is a potent inducer of apoptosis in transformed and tumor cell lines, but usually not in other cells. Here we present a study on the effect of TRAIL on cultured keratinocytes. It is shown that differentiated and undifferentiated keratinocytes undergo apoptosis after addition of TRAIL to the medium as determined by morphologic and biochemical criteria, such as cellular shrinkage and activation of caspases. The sensitivity for TRAIL differs greatly between undifferentiated and differentiating keratinocytes, however, with undifferentiated cells being much more susceptible to apoptosis. Commitment to terminal differentiation in the absence of TRAIL does not in itself induce apoptosis. In contrast to the promyelocytic cell line HL60, internucleosomal DNA fragmentation is not observed in keratinocytes, as assessed by flow cytometric analysis and agarose gel electrophoresis. Interestingly, the prime effector of DNA fragmentation, DNA fragmentation factor of 40 kDa (DFF40), is expressed in keratinocytes, yet internucleosomal cleavage fails to occur. Our data indicate that programmed cell death during keratinocyte differentiation is distinct from receptor-mediated apoptosis in response to a death ligand.
- Published
- 2003
- Full Text
- View/download PDF
50. The human cystatin M/E gene (CST6): exclusion candidate gene for harlequin ichthyosis.
- Author
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Zeeuwen PL, Dale BA, de Jongh GJ, van Vlijmen-Willems IM, Fleckman P, Kimball JR, Stephens K, and Schalkwijk J
- Subjects
- Animals, Cystatin M, DNA Mutational Analysis, Humans, Ichthyosis, Lamellar pathology, Mice, Skin pathology, Cystatins genetics, Ichthyosis, Lamellar genetics
- Abstract
Cystatin M/E is a recently discovered cysteine proteinase inhibitor whose expression is largely confined to cutaneous epithelia. In human skin it is expressed in sweat glands, hair follicles, and stratum granulosum of the epidermis where it presumably acts as a substrate for transglutaminase. Very recently we reported that a null mutation in the mouse cystatin M/E gene (Cst6) causes the murine ichq phenotype, which is characterized by abnormalities in cornification and desquamation, demonstrating an essential role for cystatin M/E in the final stages of epidermal differentiation. We here obtained the complete sequence of the human cystatin M/E gene (CST6), which provides a tool to investigate CST6 as a candidate gene in skin diseases characterized by abnormal cornification. The involvement of CST6 in harlequin ichthyosis in humans was evaluated by sequencing the entire coding region and intron-exon boundaries for mutations in 11 sporadic harlequin ichthyosis patients. No CST6 mutations were detected in this group, which comprised type 1 and type 2 harlequin ichthyosis patients. Disturbed transcription/translation due to mutations in regulatory and noncoding regions of cystatin M/E was unlikely because cystatin M/E protein expression was observed in all patients examined, as assessed by immunohistochemistry. Although our results indicate that CST6 is not a major gene contributing to type 1 and 2 harlequin ichthyosis, these data may facilitate further analysis of the role of cystatin M/E in normal human skin and other genetic disorders of cornification.
- Published
- 2003
- Full Text
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