Lin Pei, Chen Zhendong, Lu Yinying, Shi Hongyu, Lin Jun
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China.
Exp Ther Med. 2024 Feb 29;27(4):176. doi: 10.3892/etm.2024.12464. eCollection 2024 Apr.
Atopic dermatitis (AD) is a common allergic skin disease, and its pathogenesis involves genetic and environmental factors, as well as the immune response and skin barrier. PJ-001 is a small-molecule proteolysis-targeting chimera, which can degrade proteins related to the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. In the present study, 0.5% 2,4-dinitrofluorobenzene was used to induce a mouse model of AD. Following treatment with PJ-001, the number of scratches and the severity of skin damage in the AD mice were recorded. Pathological changes in skin lesions were observed with hematoxylin and eosin staining. The expression levels of JAK2/STAT3, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB), Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3) were detected using western blotting. Furthermore, reverse transcription-PCR was used to detect the mRNA expression levels of filaggrin (FLG) and keratin 17, and the change in interleukin-10 levels in the splenic tissue of the mice. Compared with in the control group, the model group exhibited severe skin lesions. Following treatment with PJ-001, the AD-like inflammation in mice decreased. The expression levels of LC3 II/LC3 I and Beclin 1 were significantly reduced (P<0.01), and the expression levels of JAK2, STAT3, TLR4 and NF-κB were significantly downregulated (P<0.001). Additionally, the mRNA expression levels of FLG were significantly upregulated (P<0.001). These results indicated that PJ-001 may alleviate the skin condition in a mouse model of AD. The underlying mechanism may involve inhibition of the JAK/STAT signaling pathway, thereby suppressing the release of inflammatory factors, reducing excessive autophagy at the site of skin lesions, and enhancing the skin barrier function. In conclusion, PJ-001 could be considered a potential therapeutic option for AD.
特应性皮炎（AD）是一种常见的过敏性皮肤病，其发病机制涉及遗传和环境因素，以及免疫反应和皮肤屏障。PJ-001是一种小分子靶向蛋白水解嵌合体，可降解与Janus激酶2/信号转导及转录激活因子3（JAK2/STAT3）通路相关的蛋白质。在本研究中，使用0.5% 2,4-二硝基氟苯诱导AD小鼠模型。用PJ-001治疗后，记录AD小鼠的抓挠次数和皮肤损伤严重程度。用苏木精和伊红染色观察皮肤病变的病理变化。采用蛋白质免疫印迹法检测JAK2/STAT3、Toll样受体4/核因子-κB（TLR4/NF-κB）、Beclin 1和微管相关蛋白1轻链3（LC3）的表达水平。此外，采用逆转录聚合酶链反应检测丝聚合蛋白（FLG）和角蛋白17的mRNA表达水平，以及小鼠脾脏组织中白细胞介素-10水平的变化。与对照组相比，模型组表现出严重的皮肤病变。用PJ-001治疗后，小鼠的类AD炎症减轻。LC3 II/LC3 I和Beclin 1的表达水平显著降低（P<0.01），JAK2、STAT3、TLR4和NF-κB的表达水平显著下调（P<0.001）。此外，FLG的mRNA表达水平显著上调（P<0.001）。这些结果表明，PJ-001可能减轻AD小鼠模型的皮肤状况。其潜在机制可能包括抑制JAK/STAT信号通路，从而抑制炎症因子的释放，减少皮肤病变部位的过度自噬，并增强皮肤屏障功能。总之，PJ-001可被视为AD的一种潜在治疗选择。
