Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.

中文翻译：

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核黄素激酶结合并激活诱导型一氧化氮合酶以重编程巨噬细胞极化


核黄素激酶 （RFK） 在核黄素代谢中是必不可少的，它将核黄素转化为黄素单核苷酸 （FMN），后者进一步加工成黄素腺嘌呤二核苷酸 （FAD）。虽然 RFK 增强了单核细胞增生李斯特菌的巨噬细胞吞噬作用，但其在巨噬细胞极化中的作用尚不清楚。我们的研究表明，RFK 缺陷在体外和体内都会损害 M（IFN-γ） 并促进 M（IL-4） 极化。从机制上讲，RFK 与诱导型一氧化氮 （NO） 合酶 （iNOS） 相互作用，后者需要 FMN 和 FAD 作为激活的辅助因子，导致 NO 产生增加，从而通过抑制三羧酸循环和线粒体电子传递链来改变能量代谢。外源性 FAD 逆转 RFK 缺陷引起的代谢和极化变化。此外，骨髓从高核黄素喂养的小鼠过继转移到野生型荷瘤小鼠中，重编程肿瘤相关的巨噬细胞极化并抑制肿瘤生长。这些结果表明，靶向 RFK-iNOS 或调节核黄素代谢可能是巨噬细胞相关免疫疾病的潜在疗法。