Riboflavin fuels NADPH oxidase 2 for defense against bacteria

What is it about?

Riboflavin, also known as vitamin B2, is converted by riboflavin kinase (RFK) into flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential cofactors of dehydrogenases, reductases, and oxidases including the phagocytic NADPH oxidase 2 (Nox2). Riboflavin deficiency is common in young adults and elderly individuals, who are at the coincidental risk for listeriosis. To address the impact of acute riboflavin deficiency on host defense against Listeria monocytogenes (L.m.), we generated conditional RFK knockout (KO) strains of mice. Phagocyte‐specific RFK KO impaired the capability of phagocytes to control intracellular L.m., which corresponded to a greater susceptibility of mice to in vivo challenge with L.m. The oxidative burst of RFK‐deficient phagocytes in response to L.m. infection was significantly reduced. Mechanistically, TNF‐induced priming of Nox2, which is needed for oxidative burst, was defective in RFK‐deficient phagocytes. Lack of riboflavin in wild‐type macrophages for only 6 h shut down TNF‐induced, RFK‐mediated de novo FMN/FAD generation, which was accompanied by diminished ROS production and impaired anti‐listerial activity. Vice versa, ROS production by riboflavin‐deprived macrophages was rapidly restored by riboflavin supplementation. Our results suggest that acute riboflavin deficiency immediately impairs priming of Nox2, which is of crucial relevance for an effective phagocytic immune response in vivo.

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Photo by Wesual Click on Unsplash

Photo by Wesual Click on Unsplash

Why is it important?

The intracellular nature of L.m. presents a therapeutic challenge because none of the antibiotics of choice penetrate the host cells, distribute within the cells, and remain stable in the intracellular environment. Thus, riboflavin supplementation should also be considered next to antibiotics as a complementary therapeutic modality of listeriosis of elderly individuals to ensure optimal ROS production by neutrophils and macrophages, which represents an effective host defense mechanism protecting young and riboflavin‐proficient individuals from listeriosis.