3.1. Metabolism and Functions
Retinol (vitamin A1) is a fat-soluble vitamin and an obligatory dietary factor since it is not synthesized de novo by humans. The main vitamin A sources are organ meats, milk, cheese; in green vegetables and yellow fruits are present provitamin A carotenoids, which must be cleaved to retinal before absorption [15]. Preformed vitamin A (retinol, retinal, retinoic acid, and retinyl ester) is hydrolysed into retinol in the lumen of the small intestine. Retinol is esterified in the enterocyte and packaged into chylomicrons, and the liver represents the main site of chylomicron vitamin A storage. During a deficiency status, vitamin A stores are mobilized, and retinol circulate bound to the retinol-binding protein (RBP) and is utilized by target tissues [15].
The functions of vitamin A are mediated by all-trans-retinoic acid, which, by binding specific nuclear transcription factors, (retinoid receptors) regulates the expression of several hundred genes [15,16,17,18,19]. Vitamin A-regulated genes are involved in fundamental biological activities, playing an important role in supporting vision, growth, cell, and tissue differentiation, haematopoiesis and immunity.
Regarding immunity, vitamin A contributes to supporting the integrity of epithelia, particularly the gastrointestinal epithelia tissue among children suffering from severe infections or who are undernourished [15]. Vitamin A is also important in regulating the number and function of natural killer (NK) cells, macrophages, and neutrophils [16,17]. By downregulating the expression level of interferon (IFN)-γ and upregulating the secretion of inerleukin (IL)-5, vitamin A plays a regulatory role in the early differentiation stage of NK cells. Moreover, it regulates the differentiation of dendritic cells precursors and promotes the secretion of the pro-inflammatory cytokines IL-12 and IL-23 by dendritic cells. It has also a crucial role in promoting Foxp3+ Treg generation, while reciprocally inhibiting Th1/Th17 generation and a Th9 transcriptional and epigenomic program [20,21]. Furthermore, vitamin A is involved in the antimicrobial action of macrophages, playing a role in the phagocytic and oxidative burst activity [13].
Vitamin A also supports adaptive immunity. Indeed, retinoids represents physiological modulators of normal B cell growth and differentiation, thus vitamin A deficiency negatively affects B cell function [18]. Furthermore, animal studies have shown impairment in the antibody response due to vitamin A deficiency [19]. The production of antibodies may be enhanced by the influence of vitamin A on T helper 2 cells development [22] and antigen-presenting cells [15,23]. In addition, retinoids induce the differentiation of Tregs and maintain both the stability of Tregs and their immunoregulatory function [24]. Indeed, retinoids play fundamental roles in cell-mediated immunity, representing an important cofactor in T cell activation [25] and influencing the expression of membrane receptors that mediate T-cell signalling [17]. Vitamin A supplementation trials conducted in paediatric populations have shown the potential effect to increase T-cell, particularly of the CD4 subpopulation [15,26].