An example of the involvement of vitamin D metabolites in monocytes of the innate system is shown in Figure 1. In this example of subjects with tuberculosis, the pathogen Mycobacterium tuberculosis has invaded monocytes and macrophages and activated their plasma membrane toll-like receptors. This results in the gene transcription production of both the VDR and the mitochondrial 25(OH)D-1α-hydroxylase. Next the 25(OH)D in the serum that has migrated into the monocyte’s cytosol and then into the mitochondria of the monocytes will be converted to the steroid hormone 1α,25(OH)2D3. Next, the VDR+ bound 1α,25(OH)2D3, acting through genomic responses, activates the synthesis of the immune surveillance protein molecule, cathelicidin, which then engages in the expression and activation of autophagy (cell breakdown) related to the tuberculosis infection. It is the internalization of the pathogen by the phagosomes and its subsequent breakdown that results in the pathogen’s death.
Fig1. Activation of a monocyte’s or macrophage’s toll-like signaling receptors by infection by a pathogen like Mycobacterium tuberculosis; involvement of circulating 25(OH)D3, and local 1α,25(OH)2D3 and local VDR. For the innate immune system’s dendritic cells, the key players are toll-like receptors that are single, membrane-spanning receptors that recognize and bind as a ligand structurally conserved molecules only derived from invading microbes. This initiates signal transduction pathways that lead to the suppression or induction of genes that orchestrate the inflammatory response against the invading pathogen. In this figure, a genomic increase in the production of the mitochondrial 25(OH) D3-1α-hydroxylase results in an increased production of 1α,25(OH)2D3. This newly synthesized 1α,25(OH)2D3 binds to the VDR and stimulates the production of cathelicidins that are essential for killing the Mycobacterium tuberculosis pathogen cells. Grey circles, individual invading M. tuberculosis microbes; small grey circles, killed M. tuberculosis microbes; pink triangles, newly synthesized cathelicidin molecules; green circles, 25(OH)D3; red circles, 1α,25(OH)2D3; blue half-moon, 25-hydroxyvitamin D3-1α-hydroxylase; purple icon, the vitamin D receptor (VDR) for 1α,25(OH)2D3. Modified from M. Hewison, Rheum. Dis. Clin. North Am. 38 125 (2012).
If the individual with tuberculosis is vitamin D deficient to the extent that the plasma 25(OH)D level is low (e.g., ~10 ng/mL; see Figure 2), then there will be insufficient levels of 25(OH)D available to empower the 25(OH)D3 1α-hydroxylase to produce adequate levels of 1α,25(OH)2D3 required for the genomic pro duction of cathelicidins. In the absence of adequate levels of cathelicidin the autophagy innate response will be weak and ineffective.
Fig2. A summary of the contributions of the vitamin D endocrine system to good health. 1α,25(OH)2D3, enzymatically produced by either the kidney or paracrine 25(OH)D3-1α-hydroxylase, is carried throughout the blood compartment by the vitamin D binding protein (DBP). The 1α,25(OH)2D3 enters any of the some 30 cell types that are known to contain the vitamin D receptor (VDR) and stimulates a variety of genomic and rapid responses that can contribute to good health. These responder cell types are organized, in the left-hand column (light green color), into five primary vitamin D-dependent physiological systems. The 1α,25(OH)2D3 brain system is at the present time only studied in rodent systems. The center column tabulates for each of the five major vitamin physiological systems the nature of their biological responses. The right hand column lists known examples of vitamin D deficiency related diseases that are “associated” with each physiological system. In general, only for the calcium homeostasis physiological system have randomized clinical trials (with humans) been carried out showing that correction of the vitamin D deficiency by increased vitamin D3 intake can minimize the disease studied. The blood levels of 25(OH)D have been shown to be correlated with varying extents of vitamin D deficiency. The inset table (bottom left) summarizes, for humans, the changes in the circulating levels of 25(OH)D that are linked to varying degrees of vitamin D deficiency (from severe to insufficient to sufficient, etc.). From a clinical perspective this information can be utilized to determine the recommended daily intake of vitamin D3 to maintain good vitamin D health.
