Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts

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.

Lives of Skin Lesions in Monkeypox: Histomorphological, Immunohistochemical, and Clinical Correlations in a Small Case Series

“…This phenomenon is called immunothrombosis and has been described in other viral diseases, for example, in COVID-19 [ 43 , 44 , 45 ]. We have recently also observed this mechanism in the treatment of ano-genital warts with ingenol mebutate [ 46 ]. Obliterating the vascular changes typically causes a strong ischemic pain and therefore might be the histopathologic correlate for the sometimes-massive pain that mpox patients report.…”

Ingenol mebutate–associated immune thrombocytopenic purpura

“…In addition, it has been used off-label for anogenital warts. 1 It is derived from the sap of the Euphorbia peplus plant and has historically had therapeutic use for a variety of skin conditions. The drug causes rapid necrosis in as little as 1 day after application by increasing intracellular and mitochondrial calcium, triggering cellular swelling and loss of membrane integrity.…”