Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis.
Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis.
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DOI：
10.3389/fimmu.2022.1094375
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发表时间：
2022
影响因子：
7.3
通讯作者：
Chen, Hongxiang
中科院分区：
文献类型：
--
作者：
Kong, Yi;Jiang, Jian;Huang, Yuqiong;Liu, Xin;Jin, Zilin;Li, Li;Wei, Fen;Liu, Xinxin;Yin, Jie;Zhang, Yonghui;Tong, Qingyi;Chen, Hongxiang
牛皮癣是一种常见的炎症性皮肤病，被世界卫生组织认定为"一种不可治愈的慢性、非传染性、疼痛、毁容和致残性疾病。"代谢综合征（MetS）是银屑病最常见和最重要的合并症，这一事实表明脂质代谢在银屑病发病机制中起着重要作用。Narciclasine（Ncs）是从石蒜科植物中分离得到的生物碱。其生物活性包括抗肿瘤、抗菌、抗血管生成、促进能量消耗以改善饮食诱导的肥胖。在这里，我们报告说，Ncs可能是银屑病的潜在候选人，在生物体和细胞水平上发挥作用。在IMQ诱导的银屑病样小鼠模型中评估Ncs的治疗效果。然后，通过体外实验，探讨Ncs对HaCaT细胞增殖和Th17细胞极化的抑制作用;采用转录组学和脂质组学分析Ncs作用的主要靶点;采用单细胞测序数据鉴定Ncs作用的靶细胞。ncs可以通过抑制银屑病相关的炎症介质来抑制角质形成细胞的增殖和减少皮肤中免疫细胞的募集。此外，它对Th17细胞极化显示出直接抑制作用。转录组学和脂质组学数据进一步揭示Ncs广泛调节脂质代谢相关基因，尤其是磷脂酶A2（PLA2）家族，并增加脂质分子。结合单细胞数据分析，我们证实角质形成细胞是Ncs发挥功能的主要细胞。综上所述，我们的研究结果表明，Ncs减轻小鼠银屑病样皮肤炎症，这与抑制角质形成细胞中的PLA2和改善磷脂代谢有关。ncs作为一种新型抗银屑病药物具有进一步开发的潜力。
Psoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels. The therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action. Ncs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions. Taken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.
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