Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts
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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.
in: INT J MOL SCI, Jahrgang 23, Nr. 21, 13377, 02.11.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts
AU - Braun, Stephan A
AU - Bauer, Alexander T
AU - Németh, Csongor
AU - Rózsa, Annamária
AU - Rusch, Louisa
AU - Erpenbeck, Luise
AU - Schloer, Sebastian
AU - Silling, Steffi
AU - Metze, Dieter
AU - Gerber, Peter A
AU - Schneider, Stefan W
AU - Gyulai, Rolland
AU - Homey, Bernhard
PY - 2022/11/2
Y1 - 2022/11/2
N2 - 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.
AB - 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.
KW - Humans
KW - Papillomavirus Infections/complications
KW - Condylomata Acuminata/drug therapy
KW - Diterpenes/pharmacology
KW - Keratosis, Actinic/drug therapy
KW - Warts
KW - Papillomaviridae
KW - Necrosis
KW - Skin Abnormalities
U2 - 10.3390/ijms232113377
DO - 10.3390/ijms232113377
M3 - SCORING: Journal article
C2 - 36362165
VL - 23
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 21
M1 - 13377
ER -