法国居里研究所Raphaël Rodriguez研究组发现驱动炎症的一条可药用铜信号通路。该研究于2023年4月26日在线发表于国际一流学术期刊《自然》。

研究人员表明，细胞表面糖蛋白CD44在发育、免疫和癌症进展的背景下标志着不同细胞表型的获得，它介导了包括铜在内的金属的吸收。研究人员在炎症巨噬细胞的线粒体中发现了一个化学活性铜（II）池，通过激活过氧化氢来催化NAD（H）氧化还原循环。NAD⁺的维持使代谢和表观遗传程序朝着炎症状态发展。用合理设计的二甲双胍（LCC-12）针对线粒体铜（II），诱导NAD（H）池的减少，导致反对巨噬细胞激活的代谢和表观遗传状态。LCC-12在其他场合干扰细胞的可塑性，并在细菌和病毒感染的小鼠模型中减少炎症。这项工作强调了铜作为细胞可塑性调节器的核心作用，并揭示了一种基于代谢重编程和控制表观遗传细胞状态的治疗策略。

研究人员表示，炎症是一个复杂的生理过程，是对有害刺激的反应。它涉及免疫系统的细胞，能够清除损伤源和受损组织。过度的炎症可因感染而发生，是一些疾病的标志。炎症反应的分子基础并不完全了解。

附：英文原文

Title: A druggable copper-signalling pathway that drives inflammation

Author: Solier, Stphanie, Mller, Sebastian, Caeque, Tatiana, Versini, Antoine, Mansart, Arnaud, Sindikubwabo, Fabien, Baron, Leeroy, Emam, Laila, Gestraud, Pierre, Panto, G. Dan, Gandon, Vincent, Gaillet, Christine, Wu, Ting-Di, Dingli, Florent, Loew, Damarys, Baulande, Sylvain, Durand, Sylvre, Sencio, Valentin, Robil, Cyril, Trottein, Franois, Pricat, David, Nser, Emmanuelle, Cougoule, Cline, Meunier, Etienne, Bgue, Anne-Laure, Salmon, Hlne, Manel, Nicolas, Puisieux, Alain, Watson, Sarah, Dawson, Mark A., Servant, Nicolas, Kroemer, Guido, Annane, Djillali, Rodriguez, Raphal

Issue&Volume: 2023-04-26

Abstract: Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2,3,4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

DOI: 10.1038/s41586-023-06017-4

Source: https://www.nature.com/articles/s41586-023-06017-4