Extending the IMQ Model: Deep Characterization of the Human TLR7 Response for Early Drug Development.

IF 4.5 2区 医学 Q2 CELL BIOLOGY
Juliette A van den Noort, Salma Assil, Micha N Ronner, Michelle Osse, Iris Pot, Yalçin Yavuz, Jeffrey Damman, Erik Lubberts, Robert Rissmann, Tessa Niemeyer-van der Kolk, Ingrid Tomljanovic, Manon A A Jansen, Matthijs Moerland
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Abstract

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.

Abstract Image

扩展 IMQ 模型:深入表征人类 TLR7 反应,促进早期药物开发。
咪喹莫特(IMQ;品牌名 Aldara®)是一种注册外用制剂,已被证实可通过 Toll 样受体 (TLR)7 途径诱发局部炎症。本研究的目的是描述健康志愿者局部接触 IMQ 7 天(168 小时)后 TLR7 介导的炎症,并比较短期接触(48 小时-72 小时)和长期接触(120 小时-168 小时)的效果。在闭塞状态下,将 IMQ(100 毫克)涂抹在 10 名健康参与者背部 5 个不同的胶带粘贴治疗部位,最多连续涂抹 7 天。每天测量红斑和皮肤灌注情况,直至 168 小时。在施用 IMQ 后的 0 小时、48 小时、72 小时、120 小时和 168 小时采集活组织样本进行免疫组化染色和 RNA 测序。IMQ 在使用后 48 小时开始引发炎症反应,包括皮肤红斑和灌注。在转录组水平上,IMQ 诱导 TLR7 信号、IRF 参与和通过 NF-κB 激活 TNF 信号。此外,长期接触 IMQ 后,细胞水平的炎症反应增强,树突状细胞、巨噬细胞和 T 细胞浸润,转录组图谱也证实了这一点。与 72 小时相比,接触 IMQ 168 小时后的红斑和灌注反应没有差异。与短时间暴露相比,长时间暴露于 IMQ 会增强细胞反应,并增加调节活性的途径,因此可以作为针对先天性和适应性免疫反应的研究化合物的模型。
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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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