Luo Qingyan, Wang Xiaoheng, Zhang Yanling, Xie Wenrong, Liang Lina, Xu Yingping, Liang Yunshen, Ji Suyun
Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
Experimental Research Center, Dermatology Hospital, Southern Medical University, Guangzhou, China.
J Dermatol Sci. 2025 Mar;117(3):71-80. doi: 10.1016/j.jdermsci.2025.02.001. Epub 2025 Feb 17.
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and damage, immune dysregulation and fibrosis. Endothelial mesenchymal transition (EndoMT) has been implicated in the skin fibrosis of SSc. Many studies have demonstrated that janus kinase type2 (JAK2) inhibitor can alleviate skin fibrosis in both SSc patients and bleomycin (BLM)-induced mouse models of SSc. However, the potential therapeutic effect of JAK2 inhibitor on EndoMT in SSc skin, along with the underlying molecular mechanisms, remains unexplored.
To investigate the effects of JAK2 inhibitor on the EndoMT in SSc skin and to elucidate the associated molecular mechanisms.
Wild-type female C57BL/6 mice were divided into several groups to assess the effects of JAK2 inhibitor on EndoMT through H&E staining, masson staining, immunofluorescence and single-cell RNA-sequencing (scRNA-seq). Cultured human umbilical vein endothelial cells (HUVECs) were used to explore the mechanism of action of JAK2 inhibitor on EndoMT using immunofluorescence, quantitative RT-PCR, RNA sequencing and western blot.
JAK2 inhibition improved skin fibrosis, reduced CD31/α-SMA co-localisation and the number of EndoMT-activated vascular endothelial cells in bleomycin-induced SSc mice. Treatment of HUVECs with TGF-β or BLM led to a myofibroblast-like morphology and markers, along with downregulation of endothelial cell features, which were reversed following JAK2 inhibition. The activation of the PI3K/Akt/mTOR pathway was involved in EndoMT in HUVECs induced by TGF-β/BLM, and this activation was attenuated by JAK2 inhibition.
JAK2 inhibitor may serve as an effective treatment for EndoMT in SSc, potentially through modulation of the PI3K/Akt/mTOR signaling pathway.
系统性硬化症（SSc）是一种自身免疫性疾病，其特征为血管内皮功能障碍与损伤、免疫失调及纤维化。内皮-间充质转化（EndoMT）与SSc的皮肤纤维化有关。许多研究表明，Janus激酶2（JAK2）抑制剂可减轻SSc患者及博来霉素（BLM）诱导的SSc小鼠模型的皮肤纤维化。然而，JAK2抑制剂对SSc皮肤中EndoMT的潜在治疗作用及其潜在分子机制仍未得到探索。
研究JAK2抑制剂对SSc皮肤中EndoMT的影响，并阐明相关分子机制。
将野生型雌性C57BL/6小鼠分为几组，通过苏木精-伊红染色、Masson染色、免疫荧光和单细胞RNA测序（scRNA-seq）评估JAK2抑制剂对EndoMT的影响。使用培养的人脐静脉内皮细胞（HUVECs），通过免疫荧光、定量逆转录-聚合酶链反应、RNA测序和蛋白质免疫印迹法探索JAK2抑制剂对EndoMT的作用机制。
JAK2抑制改善了博来霉素诱导的SSc小鼠的皮肤纤维化，减少了CD31/α-平滑肌肌动蛋白（α-SMA）共定位以及EndoMT激活的血管内皮细胞数量。用转化生长因子-β（TGF-β）或BLM处理HUVECs会导致其呈现成肌纤维细胞样形态和标志物，同时内皮细胞特征下调，而JAK2抑制后这些变化得到逆转。磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的激活参与了TGF-β/BLM诱导的HUVECs中的EndoMT，且这种激活被JAK2抑制所减弱。
JAK2抑制剂可能是治疗SSc中EndoMT的有效药物，可能是通过调节PI3K/Akt/mTOR信号通路实现的。
