基于咪喹莫的外用乳膏可用作乳头瘤和多种皮肤肿瘤的免疫刺激剂。咪喹莫被认为是TLR7受体配体。这些乳膏还可用于研究，用以在小鼠中诱导皮肤炎症作为银屑病的模型。我们观察到，这种炎症反应不完全依赖于咪喹莫，并着手确定哪些成分驱动了促炎症效应。为此，我们在BALB/cJRj小鼠模型中检查诱导反应，在该模型中，将50毫克乳膏涂抹在2平方厘米的皮肤上（125毫克/千克咪喹莫-5％W/V，和/或625毫克/千克异壳基油酸-25％W/V）。比较含异壳基油酸、咪喹莫和两者组合的乳膏制剂，我们观察到异壳基油酸在2天内引起皮肤炎症，而咪喹莫需要5天才出现初步迹象。异壳基油酸激活了炎症小体反应，刺激了促炎症细胞因子释放并上调了IL-23/17轴。接受异壳基油酸治疗的动物肝脏增大（+ 40％重量），但咪喹莫单独未观察到这种情况。咪喹莫易于代谢和清除血浆和肝脏，但在全身皮肤中保持高水平（于涂抹区域为200 mM；在未处理的皮肤中为200 µM）。咪喹莫应用与脾脏肿大、细胞因子诱导/释放和初期体重下降有关，持续时间为3天。尽管整个动物皮肤中的咪喹莫水平都很高，但只有在治疗区域才会出现炎症，并且比异壳基油酸组轻微。由于这些区域的浓度远高于体外所需的10 µM，这意味着咪喹莫引起的皮肤炎症是由于其它效应（如腺苷受体激动）而不是TLR7激动。在大脑中，异壳基油酸未引起明显的细胞因子表达变化，而咪喹莫单独轻微刺激IL-1β和CCL9的表达。然而，两者的结合导致大脑诱导CCL3、-9、CXCL10、-13、IL-1β和TNFα。这些数据的含义是异壳基油酸有助于咪喹莫或外周分泌的细胞因子进入大脑。我们的数据表明，小鼠的银屑病样皮肤反应更多地受异壳基油酸驱动，而不是一般所报道的，而模型中使用的剂量和路线导致了深刻的全身效应，这可能使药物效应的解释更加复杂。 ©2023年，作者独家许可Springer Nature Switzerland AG发行。

Topical imiquimod based creams are indicated as immune stimulants for papillomas and various skin neoplasms. Imiquimod is considered a TLR7 ligand. These creams are also used in research to induce skin inflammation in mice as a model for psoriasis. We observed that this inflammatory response was not strictly imiquimod dependent and we set out to establish which components drive the proinflammatory effects. To this end, we examined the induction response in a BALB/cJRj mouse model, in which 50 mg of cream is applied to 2 cm2 of skin (125 mg/kg imiquimod-5% W/V, and/or 625 mg/kg isostearic acid-25% W/V). Comparing cream formulations containing isostearic acid, imiquimod and the combination, we observed that isostearic acid causes skin inflammation within 2 days, whereas imiquimod requires up to 5 days for initial signs. Isostearic acid activated an inflammasome response, stimulated release of proinflammatory cytokines and upregulated the IL-23/17 axis. Animals treated with isostearic acid had enlarged livers (+ 40% weight), which was not observed with imiquimod alone. Imiquimod was readily metabolized and cleared from plasma and liver, but was maintained at high levels in the skin throughout the body (200 mM at area of application; 200 µM in untreated skin). Imiquimod application was associated with splenomegaly, cytokine induction/release and initial body weight loss over 3 days. Despite high imiquimod skin levels throughout the animal, inflammation was only apparent in the treated areas and was less severe than in isostearic acid groups. As the concentrations in these areas are well above the 10 µM required for TLR7 responses in vitro, there is an implication that skin inflammation following imiquimod is due to effects other than TLR7 agonism (e.g., adenosine receptor agonism). In brain, isostearic caused no major changes in cytokine expression while imiquimod alone sightly stimulated expression of IL-1β and CCL9. However, the combination of both caused brain induction of CCL3, -9, CXCL10, -13, IL-1β and TNFα. The implication of these data is that isostearic acid facilitates the entry of imiquimod or peripherally secreted cytokines into the brain. Our data suggest that psoriaform skin responses in mice are more driven by isostearic acid, than generally reported and that the dose and route used in the model, leads to profound systemic effects, which may complicate the interpretation of drug effects in this model.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.