Matrix metalloproteinase landscape in the imiquimod-induced skin inflammation mouse model

Inflammation and autoimmunity are known as central processes in many skin diseases, including psoriasis. It is therefore important to develop pre-clinical models that describe disease-related aspects to enable testing of pharmaceutical drug candidates and formulations to essentially develop safe and effective treatments. A widely accepted pre-clinical model of psoriasis is the imiquimod (IMQ)-induced skin inflammation mouse model. It is primarily used to assess safety and efficacy of drug candidates for treatment of psoriasis but can also be used to evaluate the performance of drug delivery systems. In this model, topically applied IMQ provokes local skin inflammation, which is characterized by elevated levels of cytokines and chemokines, cellular infiltration, and increased epidermal thickness. In this study, we investigated the abundance of a subset of matrix metalloproteinases (MMPs) in skin from mice with IMQ-induced skin inflammation and skin from naïve mice using targeted proteomics. Our findings revealed a significant increase in the abundance of MMP-2, MMP-7, MMP-8, and MMP-13 after treatment with IMQ compared to the control skin, while MMP-3, MMP-9, and MMP-10 were exclusively detected in the IMQ-treated skin. The increased abundance and broader representation of MMPs in the IMQ-treated skin provide valuable insight into the pathophysiology of skin inflammation in the IMQ model. Specifically, the changes in the MMP profiles observed in the IMQ-treated skin resemble the MMP patterns found in skin lesions of individuals with psoriasis. Ultimately, the differences in MMP abundance under IMQ-induced inflammation as compared to non-inflamed control skin can be exploited as a model to investigate drug efficacy or performance of drug delivery systems.

炎症与自身免疫是包括银屑病（psoriasis）在内的多种皮肤疾病的核心病理过程。因此，构建能够模拟疾病相关特征的临床前模型，用于筛选药物候选化合物与制剂、开发安全有效的治疗方案，具有重要的研究价值。目前被广泛认可的银屑病临床前模型为咪喹莫特（imiquimod, IMQ）诱导的皮肤炎症小鼠模型，该模型主要用于评估银屑病治疗药物候选物的安全性与有效性，同时也可用于评价药物递送系统的性能。在此模型中，局部外用咪喹莫特可诱发局部皮肤炎症，其特征为细胞因子与趋化因子水平升高、炎性细胞浸润以及表皮厚度增加。本研究通过靶向蛋白质组学（targeted proteomics）技术，检测了咪喹莫特诱导皮肤炎症的小鼠与未经处理小鼠皮肤组织中特定亚型基质金属蛋白酶（matrix metalloproteinases, MMPs）的表达丰度。结果显示，与对照组皮肤组织相比，经咪喹莫特处理的小鼠皮肤中，MMP-2、MMP-7、MMP-8及MMP-13的表达丰度显著上调；而MMP-3、MMP-9及MMP-10仅在咪喹莫特处理的皮肤组织中被检出。咪喹莫特处理组皮肤中基质金属蛋白酶表达丰度的升高与亚型覆盖范围的拓展，为解析该模型中皮肤炎症的病理生理学机制提供了重要参考。具体而言，咪喹莫特处理组皮肤的基质金属蛋白酶谱变化，与银屑病患者皮损组织中的基质金属蛋白酶模式高度相似。综上，与非炎症性对照组皮肤相比，咪喹莫特诱导的炎症皮肤中基质金属蛋白酶丰度的差异，可作为研究药物疗效或药物递送系统性能的理想模型。