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Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts
Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohist...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9656782/ https://www.ncbi.nlm.nih.gov/pubmed/36362165 http://dx.doi.org/10.3390/ijms232113377 |
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author | Braun, Stephan A. Bauer, Alexander T. Németh, Csongor Rózsa, Annamária Rusch, Louisa Erpenbeck, Luise Schloer, Sebastian Silling, Steffi Metze, Dieter Gerber, Peter A. Schneider, Stefan W. Gyulai, Rolland Homey, Bernhard |
author_facet | Braun, Stephan A. Bauer, Alexander T. Németh, Csongor Rózsa, Annamária Rusch, Louisa Erpenbeck, Luise Schloer, Sebastian Silling, Steffi Metze, Dieter Gerber, Peter A. Schneider, Stefan W. Gyulai, Rolland Homey, Bernhard |
author_sort | Braun, Stephan A. |
collection | PubMed |
description | Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors. |
format | Online Article Text |
id | pubmed-9656782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96567822022-11-15 Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts Braun, Stephan A. Bauer, Alexander T. Németh, Csongor Rózsa, Annamária Rusch, Louisa Erpenbeck, Luise Schloer, Sebastian Silling, Steffi Metze, Dieter Gerber, Peter A. Schneider, Stefan W. Gyulai, Rolland Homey, Bernhard Int J Mol Sci Article Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors. MDPI 2022-11-02 /pmc/articles/PMC9656782/ /pubmed/36362165 http://dx.doi.org/10.3390/ijms232113377 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Braun, Stephan A. Bauer, Alexander T. Németh, Csongor Rózsa, Annamária Rusch, Louisa Erpenbeck, Luise Schloer, Sebastian Silling, Steffi Metze, Dieter Gerber, Peter A. Schneider, Stefan W. Gyulai, Rolland Homey, Bernhard Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts |
title | Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts |
title_full | Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts |
title_fullStr | Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts |
title_full_unstemmed | Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts |
title_short | Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts |
title_sort | immunothrombotic mechanisms induced by ingenol mebutate lead to rapid necrosis and clearance of anogenital warts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9656782/ https://www.ncbi.nlm.nih.gov/pubmed/36362165 http://dx.doi.org/10.3390/ijms232113377 |
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