Review
Vitamin D metabolism and innate immunity

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Abstract

Effects of vitamin D on the immune system have been recognized for over 30 years and stemmed in part from analysis of the dysregulated vitamin D metabolism associated with granulomatous diseases. However, it is only in more recent years that a role for interaction between vitamin D and normal immune function has been proposed. As with the original studies, the basis for this new perspective on immunomodulation by vitamin D stems from studies of vitamin D metabolism by immune cells. In particular, induction of the vitamin D-activating enzyme CYP27B1 in monocytes via pathogen recognizing receptors has highlighted an entirely new function for vitamin D as a potent inducer of antibacterial innate immune responses. This has prompted a new potential role for vitamin D in protecting against infection in a wide range of tissues but has also prompted revision of the parameters for adequate vitamin D status. The following review describes some of the key developments in innate immune responses to vitamin D with particular emphasis on the role of key metabolic enzyme as determinants of localized immune activity of vitamin D.

Highlights

► Recent research has recognized an important role of vitamin D in maintaining normal immune function. ► CYP27B1 induction in monocytes highlights a new function for vitamin D as an inducer of antibacterial innate immune responses. ► Vitamin D also regulates antigen-presenting dendritic cells and influences T cell function. ► The present review describes key facets of vitamin D innate immunity, focusing on monocyte metabolism of vitamin D.

Introduction

Non-classical responses to vitamin D have been recognized for more than a quarter of a century ago since various neoplastic cell lines were shown to exhibit specific binding for the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) (Eisman et al., 1979, Manolagas et al., 1980). Subsequent studies showed that this interaction between 1,25(OH)2D and its cognate nuclear receptor, the vitamin D receptor (VDR), promoted antiproliferative and prodifferentiation responses in cancer cells (Colston et al., 1981, Abe et al., 1981). These data highlighted an entirely new facet of vitamin D action distinct from its effects on calcium homeostasis and bone metabolism. The range of non-classical responses to vitamin D was then extended to include actions on cells from the immune system (Abe et al., 1983, Bhalla et al., 1984). This stemmed initially from the observation that some patients with the granulomatous disease sarcoidosis present with elevated circulating levels of 1,25(OH)2D and associated hypercalcemia (Bell et al., 1979, Papapoulos et al., 1979). In these patients the high serum 1,25(OH)2D arises from elevated activity of the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1). However, in contrast to normal subjects where 1α-hydroxylase activity is classically localized in the kidney, the increased production of 1,25(OH)2D in granulomatous disease patients involves expression of CYP27B1 in disease-associated macrophages (Barbour et al., 1981, Adams et al., 1983, Adams and Gacad, 1985). Studies carried out at about the same time showed that VDR expression is common to macrophages, T-lymphocytes (T-cells), B-lymphocytes (B-cells) and other cell types from the immune system (Bhalla et al., 1983, Provvedini et al., 1983). Based on these observations it was concluded that the immune system has the potential to synthesize 1,25(OH)2D and elicit intracrine or paracrine responses from immune cells expressing the VDR (Hewison, 1992).

Subsequent studies showed that dysregulation of 1,25(OH)2D synthesis was not restricted to sarcoidosis but was a common feature of many granulomatous disorders and some forms of cancer (Hewison et al., 2007). In a similar fashion, studies in vitro showed that it was possible to potently regulate a range of immune cell functions using 1,25(OH)2D or its synthetic analogs (Griffin et al., 2003, Van Etten et al., 2003). Despite these advances, the extent to which vitamin D could act as a physiological regulator of normal immune responses remained elusive, even though expression of CYP27B1 was reported in a diverse array of non-classical target tissues (Zehnder et al., 2001). A breakthrough in the link between vitamin D physiology and normal immune function occurred 5 years ago with the first studies linking vitamin D and antibacterial activity in monocytes. The crucial feature of this new perspective on vitamin D and immunology arose from the ability of monocyte pathogen recognition receptors (PRR) to trigger localized metabolism of the precursor form of vitamin D, 25-hydroxyvitamin D (25OHD). The resulting synthesis of 1,25(OH)2D was sufficient to promote intracrine activation of VDR responses, and concomitant induction of innate immune responses. In view of the fact that 25OHD is the major circulating form of vitamin D, these observations provided a clear potential link between vitamin D status (serum 25OHD) and the efficacy of immune response. The aim of the current review will be to detail these developments with specific emphasis on the role of vitamin D metabolism as the central component of the interface between vitamin D and the immune system.

Section snippets

Vitamin D metabolism and innate immunity

The innate immune system is the body’s first line of the defence against pathogenic challenge, and occurs in an immediate and non-specific manner. Innate immune response to infection involves the complement system, antibacterial responses by neutrophils and macrophages, but also incorporates antigen presentation to lymphocytic cells from the adaptive or acquired immune system. Accumulating evidence indicates that vitamin D is involved in regulating various components of the innate immune

Alternative target cells for antibacterial activities of vitamin D

A wide range of cell types express PRRs and have the potential to initiate innate immune responses to infection. In addition to monocytes and macrophages, granulocytic cells such as neutrophils are the most abundant of all the leukocytes and therefore form the first line of response to infection. Initial reports of 1,25(OH)2D-induced LL37 expression in vitro indicated that this response occurred in neutrophils as well as monocytes (Wang et al., 2004). Neutrophils express VDR but, unlike

Alternative antibacterial targets for vitamin D

The induction of LL37 transcription by 1,25(OH)2D occurs following interaction of the liganded VDR with a consensus vitamin D response element (VDRE) within the proximal promoter of the LL37 gene (Wang et al., 2004, Gombart et al., 2005). VDR interaction with the LL37 gene promoter is observed in humans and apes, as well as New World and Old World primates. However, other non-primate mammals such as mice lack the appropriate LL37 proximal promoter VDRE and do not appear to induce the

Dendritic cells and antigen presentation

Innate immune responses to infection are not restricted to antibacterial activity in monocytes, neutrophils and other cells that encounter pathogens. As outlined above, adequate immune management of infectious agents such as M. tb requires cooperation with the adaptive immune system. In order to this, lymphocytes need to be exposed to antigen from the pathogen. The most potent antigen-presenting cells (APCs) are dendritic cells (DCs), which act as the primary initiators of T-cell-mediated

Innate immunity related diseases

Historically, vitamin D-deficiency was defined primarily by presence of the bone disease rickets (osteomalacia in adults). However, more recent studies have suggested that sub-optimal vitamin D status may occur even in the absence of rachitic bone disease. A new term – vitamin D ‘insufficiency’ – has been proposed in which serum levels of 25OHD are sub-optimal (<75 nM) without necessarily impacting on skeletal homeostasis (Holick, 2007). Because circulating levels of 25OHD are a direct

Conclusions

The last 5 years have witnessed a sea-change in our perspective on how vitamin D interacts with the immune system. Prominent new data have shown that the expression and activity of vitamin D metabolizing enzymes is central to normal immune responses, providing a mechanism for localized metabolism of 25OHD to 1,25(OH)2D at sites of infection. Unlike its renal endocrine counterpart, the vitamin D metabolic machinery within the immune system is exquisitely dependent on the availability of substrate

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