Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity
Phagosomal removal of fungal melanin reprograms macrophage metabolism to promote antifungal immunity
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DOI：
10.1038/s41467-020-16120-z
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发表时间：
2020-05-08
影响因子：
16.6
通讯作者：
Carvalho, Agostinho
中科院分区：
文献类型：
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作者：
Goncalves, Samuel M.;Duarte-Oliveira, Claudio;Carvalho, Agostinho
作为对感染的反应，巨噬细胞迅速调整自己的新陈代谢，以促进糖酵解，并为专门的抗微生物效应器功能提供燃料。在这里，我们表明真菌黑色素是在感染真菌病原体烟曲霉菌期间巨噬细胞新陈代谢重新连接所必需的分子。利用药理学和遗传学工具，我们揭示了吞噬小体内黑色素对钙的隔离和有效的先天性免疫反应所需的糖酵解诱导之间的分子联系。通过重塑细胞内钙机制并通过钙调素损伤信号，黑色素通过激活低氧诱导因子1亚单位α(HIF-1α)和吞噬募集哺乳动物靶标雷帕霉素(MTOR)来驱动免疫代谢信号轴朝向糖酵解。这些数据显示了真菌感染期间巨噬细胞免疫代谢调节的关键机制，并强调了免疫细胞的代谢再利用作为一种潜在的治疗策略。巨噬细胞在炎症刺激下经历从氧化磷酸化到糖酵解的Warburg式转换。在这里，作者表明，真菌黑色素可以通过在吞噬小体中隔离钙并保护人体免受烟曲霉感染而触发人类巨噬细胞的这种转换。
In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1 alpha) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy. Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.