中国医学科学院曹雪涛团队发现，细胞精胺靶向JAK信号转导来抑制细胞因子介导的自身免疫。2024年6月21日，《免疫》杂志在线发表了这项成果。

研究人员表示，I型干扰素（IFN-I）通路的长期激活会导致系统性红斑狼疮（SLE）等自身免疫性疾病。细胞因子信号传导的代谢调控对细胞平衡至关重要。

通过对IFN-β激活的巨噬细胞进行代谢组学分析和IFN刺激反应元件报告筛选，研究人员发现精胺是Janus激酶（JAK）信号转导的代谢物制动器。精胺直接与JAK1的FERM和SH2结构域结合，损害了JAK1-细胞因子受体的相互作用，从而广泛抑制了由细胞因子IFN-I、IFN-II、白细胞介素（IL）-2和IL-6引发的JAK1磷酸化。精胺浓度降低的SLE患者的外周血单核细胞（PBMC）显示出更强的IFN-I和狼疮基因特征。

精胺治疗可减轻SLE和银屑病小鼠的自身免疫发病机制，并减少SLE患者单核细胞中的IFN-I信号传导。研究人员合成了一种精胺衍生物（精胺衍生物1[SD1]），并证明它具有强大的免疫抑制功能。这些发现揭示了精胺是细胞平衡的代谢检查点，也是控制自身免疫性疾病的潜在免疫抑制分子。

附：英文原文

Title: Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity

Author: Henan Xu, Xiao Zhang, Xin Wang, Bo Li, Hang Yu, Yuan Quan, Yan Jiang, Yuling You, Yan Wang, Mingyue Wen, Juan Liu, Min Wang, Bo Zhang, Yixian Li, Xuan Zhang, Qianjin Lu, Chu-Yi Yu, Xuetao Cao

Issue&Volume: 2024-06-21

Abstract: Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmunediseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokinesignaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-β-activatedmacrophages and an IFN-stimulated-response-element reporter screening, we identifiedspermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directlybound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction,thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II,interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individualswith SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupusgene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE andpsoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE.We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed thatit had a potent immunosuppressive function. Our findings reveal spermine as a metaboliccheckpoint for cellular homeostasis and a potential immunosuppressive molecule forcontrolling autoimmune disease.

DOI: 10.1016/j.immuni.2024.05.025

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00279-6