钾离子通道Kir2.1通过调控“代谢-表观”协同重编程促进巨噬细胞炎症性功能的机制研究

代谢和表观遗传重编程(Metabolic and Epigenetic Reprogramming)对巨噬细胞炎症性功能的发挥起到重要作用。糖代谢在炎症中的功能逐渐被证实，而它与其他代谢网络如何实现协同作用以及重构下游表观调控并诱发炎症的机制尚不明确。另外，环境因素如离子、O2、pH等如何调节免疫应答也逐渐受到重视。我们通过筛选和膜片钳实验发现巨噬细胞高表达钾离子通道Kir2.1，并证实其在巨噬细胞中的特异性敲除或阻断显著降低炎症因子的表达。代谢组和代谢流实验发现其促进糖酵解与丝氨酸、甘氨酸和一碳代谢(SGOC)网络的协同作用，并影响表观遗传调节物S-腺苷甲硫氨酸的产生及组蛋白的甲基化修饰。我们将利用体内炎症模型并结合细胞实验探讨Kir2.1促进巨噬细胞“代谢-表观”协同重编程的分子机制，为离子的炎症调控理论提供前沿探索和数据支撑，并为炎症性疾病的治疗方案提供新颖的“离子”视角和分子靶点。

Metabolic and epigenetic reprogramming plays an important role in the inflammatory function of macrophages. The function of glucose metabolism in inflammation has been gradually confirmed, however, how it works synergistically with other metabolic networks and the mechanism of reconstructing downstream epigenetic regulation and inducing inflammation is not clear. In addition, how environmental factors such as ions, O2 and pH regulate the immune response has also received increasing attention. We have previously screened with RNA-sequence and patch clamp experiments to find that potassium channel Kir2.1 was highly expressed in macrophages, and confirmed that its specific knockout or blockade in macrophages significantly suppressed the expression of inflammatory factors. Further metabolomics and metabolic flux experiments found that Kir2.1 promotes synergy between glycolysis and serine, glycine, and one-carbon metabolism (SGOC) networks, which affect the production of important epigenetic regulator S-adenosylmethionine (SAM) and methylation modification of histones. Based on this, we will combine in vivo models with cell-level experiments to deeply explore the molecular mechanism of how Kir2.1 synergistically promote the "Metabolism- Epigenetic " reprogramming of macrophages, which will provide cutting-edge exploration and data support for the theory of the regulation of inflammation and provide a new "ion" perspective and molecular targets for the treatment of inflammatory diseases.