Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany.
Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany.
Int J Mol Sci. 2022 Nov 2;23(21):13377. doi: 10.3390/ijms232113377.
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.
ingenol 美宝（IM）在治疗人乳头瘤病毒（HPV）诱导的肛门生殖器疣（AGW）方面非常有效，可在数小时内迅速消融。然而，确切的作用机制仍知之甚少。我们进行了皮肤镜检查、活体共聚焦显微镜（CLM）、组织学、免疫组织化学和免疫荧光检查，以深入了解 IM 治疗 AGW 的机制。此外，我们使用体外检测（ELISA、HPV 转染模型）进一步研究了体内发现。IM 治疗导致在 8 小时内，小血管内的中性粒细胞强烈募集和血栓形成，在某种意义上是免疫性血栓形成。体内和体外分析表明，IM 通过内皮细胞激活和血管性血友病因子（VWF）分泌，除了诱导中性粒细胞胞外陷阱（NETosis），支持促血栓形成的环境。与未感染的角质形成细胞相比，IM 在 HPV-E6/E7 转染的 HaCaT 细胞中可超诱导 CXCL8/IL-8 的表达。IM 治疗后疣的快速消融可以很好地解释为观察到的免疫性血栓形成。这种新机制迄今为止仅在 HPV 诱导的病变中观察到，与我们在光化性角化病中治疗转化角质形成细胞的机制完全不同。我们的初步研究结果表明存在 HPV 特异性效应，这对治疗其他 HPV 诱导的病变也可能具有重要意义。现在需要进行更大的研究来进一步研究 IM 在不同 HPV 肿瘤中的潜力。
