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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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