4.1. Metabolism and Functions
Vitamin C (ascorbic acid) is a water-soluble vitamin and an essential micronutrient for humans. The main sources of vitamin C are citrus fruit, tomatoes, potatoes, and green leafy vegetables. The provision of dietary vitamin C is dependent on food preparation because it is easily destroyed by prolonged storage, overcooking, and processing of foods. Breast milk represents an adequate source of vitamin C for newborns and infants.
Ascorbic acid is an antioxidant (electron donor) and is involved in several biological processes: synthesis of collagen, neurotransmitter metabolism, cholesterol metabolism, fatty acid transport (synthesis of carnitine), maintaining the iron and copper atoms, and is a cofactor of the metalloenzymes, in a reduced active state. Furthermore, vitamin C affects the cellular and immunologic functions of the hematopoietic system, due to its role in enhancing nonheme iron absorption, the transfer of iron from transferrin to ferritin, and the formation of tetrahydrofolic acid [44].
Vitamin C is an essential nutrient that influences several aspects of the immune system, particularly barrier integrity and leukocyte function [45]. The fact that vitamin C is actively accumulated into the epidermal and dermal cells and into leukocytes, via sodium-dependent transporter, suggests that the vitamin plays a crucial role within the skin and the leukocytes [46]. Vitamin C is a potent water-soluble antioxidant and plays an important role in maintaining redox homeostasis within cells and in protecting host cells against the actions of reactive oxygen species (ROS) [45], released by phagocytes in order to lead to the deactivation of viruses and the killing of bacteria. Thus, acid ascorbic as scavenger of ROS may both protect crucial cell structural components and modulate the pro-inflammatory signaling pathway activated by the oxidative burst [46,47]. Vitamin C influences innate immunity also by regulating several aspects of neutrophil function [48], particularly the chemotactic ability, as shown in several in vitro and in vivo animal studies [49,50]. Severe septic syndromes are associated with impaired neutrophil chemotactic ability [51], and studies conducted in children and neonates may suggest that it could be due also by a severe infection-induced status of vitamin C deficiency [52,53]. Furthermore, studies have shown that, in patients with recurrent infections or affected by genetic conditions such as Chediak–Higashi syndrome (CHS), supplementation with vitamin C improved significantly the antibacterial activity of neutrophils [54,55]. Ascorbic acid may also influence the apoptotic process of neutrophils, thus promoting resolution of inflammation and reducing extensive tissue damage [46]. Lastly, promising in vitro and preclinical data suggest that vitamin C supplementation could play a role on more recently discovered functions of neutrophils, such as the formation of neutrophil extracellular traps (NETs), resulting by the release of toxic intracellular components following the necrotic death of neutrophils [56]. Ascorbic acid may attenuate tissue damage reducing the formation of NETs [48].
Furthermore, vitamin C is effective in supporting both the humoral response and the cell-mediated immunity [46]. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of ROS, and ultimately microbial killing [57]. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene-regulating effects. The effect of vitamin C on cytokine generation appears to depend on the cell type and/or the inflammatory stimulant. Recent research has indicated that vitamin C treatment attenuates synthesis of the pro-inflammatory cytokines TNF, IL-6, and IL-1β [57]. In vitro studies suggest that ascorbic acid operates as potent immunostimulator of antibody production (IgM and IgG) in humans and that the intracellular ascorbic acid content is a key parameter for establishing the immune response of peripheral blood lymphocytes [58]. Other in vitro studies have shown the role of vitamin C in promoting T-cell maturation [59]. Recent research indicates the possible role of vitamin C in regulating T-cell maturation via epigenetic mechanisms involving in the ten-eleven translocations (TETs) and histone demethylation [60,61].