van den Noort Juliette A, Assil Salma, Ronner Micha N, Osse Michelle, Pot Iris, Yavuz Yalçin, Damman Jeffrey, Lubberts Erik, Rissmann Robert, der Kolk Tessa Niemeyer-van, Tomljanovic Ingrid, Jansen Manon A A, Moerland Matthijs
Centre for Human Drug Research, Zernikedreef 8, 2333CL, Leiden, The Netherlands.
Leiden University Medical Centre, Leiden, The Netherlands.
Inflammation. 2024 Aug 26. doi: 10.1007/s10753-024-02127-x.
Imiquimod (IMQ; brand name Aldara®) is a registered topical agent that has been proven to induce local inflammation via the Toll-like receptor (TLR)7 pathway. The purpose of this study was to characterize TLR7-mediated inflammation following 7 days (168 h) of topical IMQ exposure in healthy volunteers, and to compare the effects of short exposure (48 h-72 h) with prolonged exposure (120 h-168 h). IMQ (100mg) was applied under occlusion to 5 different tape-stripped treatment sites on the back of 10 healthy participants for a maximum of 7 consecutive days. Erythema and skin perfusion were measured daily up to 168h. Biopsies for immunohistochemical staining and RNA sequencing were collected at 0h, 48h, 72h, 120h and 168h post IMQ application. IMQ triggered an inflammatory response starting at 48h after application, including erythema and perfusion of the skin. At the transcriptomic level, IMQ induced TLR7 signalling, IRF involvement and activation of TNF signalling via NF-κB. Furthermore, an enhanced inflammatory response at the cellular level was observed after prolonged IMQ exposure, with cellular infiltration of dendritic cells, macrophages and T cells which was also corroborated by transcriptomic profiles. No difference was found in the erythema and perfusion response after 168h of IMQ exposure compared to 72h. Prolonged IMQ exposure revealed enhanced cellular responses and additional pathways with modulated activity compared to short exposure and can therefore be of interest as a model for investigational compounds targeting innate and adaptive immune responses.
咪喹莫特（IMQ；商品名Aldara®）是一种已注册的外用制剂，已被证明可通过Toll样受体（TLR）7途径诱导局部炎症。本研究的目的是描述健康志愿者局部应用IMQ 7天（168小时）后TLR7介导的炎症特征，并比较短时间暴露（48小时 - 72小时）与长时间暴露（120小时 - 168小时）的效果。将100mg咪喹莫特在封闭条件下应用于10名健康参与者背部的5个不同胶带剥离治疗部位，最长连续应用7天。每天测量直至168小时的红斑和皮肤灌注情况。在应用IMQ后的0小时、48小时、72小时、120小时和168小时采集用于免疫组织化学染色和RNA测序的活检样本。咪喹莫特在应用后48小时开始引发炎症反应，包括皮肤红斑和灌注增加。在转录组水平上，咪喹莫特诱导TLR7信号传导、IRF参与以及通过NF-κB激活TNF信号传导。此外，长时间应用咪喹莫特后在细胞水平观察到炎症反应增强，有树突状细胞、巨噬细胞和T细胞的细胞浸润，这也得到了转录组图谱的证实。与72小时相比，咪喹莫特暴露168小时后的红斑和灌注反应没有差异。与短时间暴露相比，长时间应用咪喹莫特显示出增强的细胞反应和更多活性受到调节的途径，因此作为针对先天性和适应性免疫反应的研究化合物模型可能具有研究价值。
