Back to the future: a new look at 'old' vitamin D

Abstract

Our perception of the vitamin D system continues to evolve. Recent studies have re-evaluated the parameters for adequate vitamin D status in humans, revealing a high prevalence of insufficiency in many populations throughout the world. Other reports have highlighted the potential consequences of vitamin D insufficiency beyond established effects on bone homeostasis. Most notably, there is now strong evidence of a role for vitamin D in modulating innate and adaptive immunities, with insufficiency being linked to infectious disease and other immune disorders. To date, signaling pathways for these new responses to vitamin D have been based on established endocrine models for active 1,25-dihydroxyvitamin D, despite present evidence for more localized, intracrine modes of action. In the following review, we provide a fresh perspective on vitamin D signaling in non-classical target cells such as macrophages by highlighting novel factors associated with the transport and action of this pluripotent secosteroid.

Figure 1

Vitamin D signaling and the regulation of macrophage innate immunity. Proposed pathways for the extracellular entry, intracellular movement, mitochondrial metabolism, and nuclear response to vitamin D during macrophage innate immune responses. Serum 25-hydroxyvitamin D (25D) bound to vitamin D-binding protein (DBP) is internalized by macrophages either through passive diffusion of ‘free’ 25D or via megalin (meg)-mediated uptake. Intracellular 25D is then translocated to mitochondrial 25-hydroxyvitamin D-1α-hydroxylase (CYP27b1) in association with constitutive heat-shock protein 70 (hsc70). The resulting 1,25-dihydroxyvitamin D (1,25D) produced by CYP27b1 is then translocated to the nucleus in conjunction with hsc70 and Bcl-2-associated athanogene (BAG-1). Within the nucleus, 1,25D binds to the vitamin D receptor (VDR), which is then able to form a heterodimer with the retinoid X receptor (RXR). Interaction between the VDR-RXR dimer and vitamin D response elements (VDRE) in the promoters of target genes such as the antimicrobial protein cathelicidin (LL37) is controlled by the VDRE-binding protein (VDRE-BP). Intracrine 1,25D-mediated transcriptional regulation of LL37 in this fashion increases availability of the antimicrobial protein for killing of bacteria in phagosomes fused with lysosomes (phago-lysosomes).