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Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris
The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279611/ https://www.ncbi.nlm.nih.gov/pubmed/35844545 http://dx.doi.org/10.3389/fimmu.2022.884248 |
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author | Kugelmann, Daniela Anders, Maresa Sigmund, Anna M. Egu, Desalegn T. Eichkorn, Ramona A. Yazdi, Amir S. Sárdy, Miklós Hertl, Michael Didona, Dario Hashimoto, Takashi Waschke, Jens |
author_facet | Kugelmann, Daniela Anders, Maresa Sigmund, Anna M. Egu, Desalegn T. Eichkorn, Ramona A. Yazdi, Amir S. Sárdy, Miklós Hertl, Michael Didona, Dario Hashimoto, Takashi Waschke, Jens |
author_sort | Kugelmann, Daniela |
collection | PubMed |
description | The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile. |
format | Online Article Text |
id | pubmed-9279611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92796112022-07-15 Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris Kugelmann, Daniela Anders, Maresa Sigmund, Anna M. Egu, Desalegn T. Eichkorn, Ramona A. Yazdi, Amir S. Sárdy, Miklós Hertl, Michael Didona, Dario Hashimoto, Takashi Waschke, Jens Front Immunol Immunology The severe autoimmune blistering disease Pemphigus vulgaris (PV) is mainly caused by autoantibodies (IgG) against desmoglein (Dsg) 3 and Dsg1. The mechanisms leading to the development of blisters are not fully understood, but intracellular signaling seems to play an important role. Sheddases ADAM10 and ADAM17 are involved in the turnover of the desmosomal cadherin Dsg2 and ADAM10 has been shown to contribute to acantholysis in a murine pemphigus model. In the present study, we further examined the role of ADAM10 and ADAM17 both in keratinocyte adhesion and in the pathogenesis of PV. First, we found that inhibition of ADAM10 enhanced adhesion of primary human keratinocytes but not of immortalized keratinocytes. In dissociation assays, inhibition of ADAM10 shifted keratinocyte adhesion towards a hyperadhesive state. However, ADAM inhibition did neither modulate protein levels of Dsg1 and Dsg3 nor activation of EGFR at Y1068 and Y845. In primary human keratinocytes, inhibition of ADAM10, but not ADAM17, reduced loss of cell adhesion and fragmentation of Dsg1 and Dsg3 immunostaining in response to a PV1-IgG from a mucocutaneous PV patient. Similarly, inhibition of ADAM10 in dissociation assay decreased fragmentation of primary keratinocytes induced by a monoclonal antibody against Dsg3 and by PV-IgG from two other patients both suffering from mucosal PV. However, such protective effect was not observed in both cultured cells and ex vivo disease models, when another mucocutaneous PV4-IgG containing more Dsg1 autoantibodies was used. Taken together, ADAM10 modulates both hyperadhesion and PV-IgG-induced loss of cell adhesion dependent on the autoantibody profile. Frontiers Media S.A. 2022-06-30 /pmc/articles/PMC9279611/ /pubmed/35844545 http://dx.doi.org/10.3389/fimmu.2022.884248 Text en Copyright © 2022 Kugelmann, Anders, Sigmund, Egu, Eichkorn, Yazdi, Sárdy, Hertl, Didona, Hashimoto and Waschke https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Kugelmann, Daniela Anders, Maresa Sigmund, Anna M. Egu, Desalegn T. Eichkorn, Ramona A. Yazdi, Amir S. Sárdy, Miklós Hertl, Michael Didona, Dario Hashimoto, Takashi Waschke, Jens Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris |
title | Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris |
title_full | Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris |
title_fullStr | Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris |
title_full_unstemmed | Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris |
title_short | Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris |
title_sort | role of adam10 and adam17 in the regulation of keratinocyte adhesion in pemphigus vulgaris |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279611/ https://www.ncbi.nlm.nih.gov/pubmed/35844545 http://dx.doi.org/10.3389/fimmu.2022.884248 |
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