title: Riboflavin (vitamin B2 ) deficiency impairs NADPH oxidase 2 (Nox2) priming and defense against Listeria monocytogenes.
abstract: 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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schramm
authors.forename: Katja
authors.initials: K
authors.lastname: Wiegmann
authors.forename: Sandra
authors.initials: S
authors.lastname: Schramm
authors.forename: Alexander
authors.initials: A
authors.lastname: Gluschko
authors.forename: Marc
authors.initials: M
authors.lastname: Herb
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000276:immunology; D005182:Flavin-Adenine Dinucleotide / Q000096:biosynthesis; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism; D012257:Riboflavin Deficiency / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D005182:Flavin-Adenine Dinucleotide; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Innate immunity; Listeriosis; NADPH oxidase (Nox2) priming; Reactive oxygen species; Riboflavin/Vitamin B2 deficiency