Environmental arginine controls multinuclear giant cell metabolism and formation
Environmental arginine controls multinuclear giant cell metabolism and formation
复制标题
DOI：
10.1038/s41467-020-14285-1
复制
发表时间：
2020-01-22
影响因子：
16.6
通讯作者：
Schabbauer, Gernot
中科院分区：
文献类型：
--
作者：
Brunner, Julia S.;Vulliard, Loan;Schabbauer, Gernot
多核巨细胞（MGC）与许多疾病有关，包括血吸虫病、结节病和关节炎。 MGC 的产生是能量密集型的，以强制膜融合和细胞质扩张。使用核因子 kappa-Beta 配体 (RANKL) 受体激活剂诱导破骨细胞生成来模拟 MGC 形成，在此我们报告 RANKL 细胞编程需要细胞外精氨酸。全身性精氨酸限制可改善多种小鼠关节炎模型的结果，其去除会诱导破骨细胞前代谢静止，与三羧酸（TCA）循环功能受损和代谢物诱导相关。精氨酸剥夺对破骨细胞生成的影响与 mTORC1 活性或整体转录和翻译抑制无关。精氨酸缺乏也会抑制 IL-4 诱导的 MGC 的产生。引人注目的是，在细胞外精氨酸缺乏的情况下，两种细胞类型都表现出灵活性，因为它们的形成可以通过选择精氨酸前体来恢复。这些数据确定了环境氨基酸如何控制多核细胞的代谢命运，并提出了操纵 MGC 相关病理和骨重塑的代谢方法。多核巨细胞（MGC）在多种疾病的发病机制中发挥着重要作用。在这里，作者证明了 MGC 形成和代谢需要细胞外氨基酸精氨酸的存在，这表明在 MGC 介导的疾病中利用全身精氨酸消耗的策略具有转化影响。
Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Beta ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling. Multinucleated giant cells (MGCs) are important in the pathogenesis of various diseases. Here, the authors demonstrate that extracellular presence of the amino acid arginine is required for MGC formation and metabolism, suggesting a translational impact for strategies utilizing systemic arginine depletion in MGC-mediated diseases.