State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Biomed Pharmacother. 2021 May;137:111373. doi: 10.1016/j.biopha.2021.111373. Epub 2021 Feb 24.
Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway.
银屑病是一种由 T 细胞介导的慢性炎症性自身免疫性疾病，其特征为角质形成细胞异常增殖和分化，以及炎症浸润。Janus 激酶-信号转导和转录激活因子（JAK-STAT）通路已被确定在介导各种生物学过程中发挥重要作用，并且与自身免疫性疾病密切相关。树突状细胞（DCs）是重要的抗原提呈细胞，在 T 细胞中发挥重要的调节作用。DCs 的增殖、分化和功能受 JAK 和 FMS 样酪氨酸激酶 3（FLT3）信号通路的调节。马来酸氟尼司他（FM）是一种由我们实验室开发的高选择性双重 JAK2/FLT3 抑制剂，对 JAK2 和 FLT3 的 IC 值分别为 0.8 nM 和 15 nM。此外，FM 是一种强效的 JAK2 抑制剂，对 JAK1 和 JAK3 的选择性分别为 863 倍和 696 倍。在这项研究中，我们评估了 FM 在体内和体外的抗银屑病活性。FM 有效抑制 HaCaT 的增殖，M5 诱导的炎症角质形成细胞，并显著抑制骨髓（BM）来源的 DC 的生成和分化，并抑制 DC 中 FLT3 的表达。FM 有效抑制耳增厚，并改善白细胞介素（IL）-23 诱导的银屑病样过度角化小鼠模型中的耳部病变。进一步在角质形成细胞 14-血管内皮生长因子（K14-VEGF）转基因纯合子小鼠模型中，FM 可明显改善银屑病症状和病理变化，显著抑制脾中 Th1 和 Th17 细胞的生成，以及耳部 DC 的积累。FM 还可显著降低 C57BL/6 和 K14-VEGF 小鼠耳部以及 K14-VEGF 小鼠血清中各种炎症因子的表达。机制表明，FM 有效抑制炎症角质形成细胞和 C57BL/6 和 K14-VEGF 小鼠耳部中 JAK2、STAT3 和 STAT5 的磷酸化，以及 K14-VEGF 小鼠耳部中 FLT3 的磷酸化。总之，FM 通过抑制 JAK2 和 FLT3 信号通路发挥出色的抗银屑病活性，包括抑制角质形成细胞增殖和调节炎症反应。
