Braun, Stephan A., Bauer, Alexander T., Nemeth, Csongor, Rozsa, Annamaria, Rusch, Louisa, Erpenbeck, Luise, Schloer, Sebastian, Silling, Steffi, Metze, Dieter, Gerber, Peter A., Schneider, Stefan W., Gyulai, Rolland ORCID: 0000-0002-3286-8846 and Homey, Bernhard ORCID: 0000-0002-5784-4146 (2022). Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts. Int. J. Mol. Sci., 23 (21). BASEL: MDPI. ISSN 1422-0067

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Braun, Stephan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, Alexander T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemeth, CsongorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rozsa, AnnamariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rusch, LouisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erpenbeck, LuiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schloer, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silling, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metze, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerber, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Stefan W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gyulai, RollandUNSPECIFIEDorcid.org/0000-0002-3286-8846UNSPECIFIED
Homey, BernhardUNSPECIFIEDorcid.org/0000-0002-5784-4146UNSPECIFIED
URN: urn:nbn:de:hbz:38-689300
DOI: 10.3390/ijms232113377
Journal or Publication Title: Int. J. Mol. Sci.
Volume: 23
Number: 21
Date: 2022
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1422-0067
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
VON-WILLEBRAND-FACTOR; PROTEIN-KINASE-C; ENDOTHELIAL-CELLS; CONDYLOMATA ACUMINATA; MELANOMA; GEL; THROMBOSIS; PROMOTES; INTERLEUKIN-8; NEUTROPHILSMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68930

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