Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization

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...

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Bibliographic Details
Published in:Redox biology 2024-12, Vol.78, p.103413, Article 103413
Main Authors: Shan, Xiao, Ji, Zemin, Wang, Baochen, Zhang, Yanan, Dong, Hongyuan, Jing, Weijia, Zhou, Yanzhao, Hu, Penghui, Cui, Yan, Li, Zihan, Yu, Sujun, Zhou, Jinxue, Wang, Ting, Shen, Long, Liu, Yuping, Yu, Qiujing
Format: Article
Language:English
Subjects:
Animals
Flavin Mononucleotide - metabolism
Flavin-Adenine Dinucleotide - metabolism
Humans
Inducible nitric oxide synthase
Interferon-gamma - metabolism
Interleukin-4 - metabolism
Macrophage Activation
Macrophage polarization
Macrophages - metabolism
Mice
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - genetics
Nitric Oxide Synthase Type II - metabolism
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Riboflavin - metabolism
Riboflavin kinase
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Summary: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.
ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2024.103413