Impact of vitamin D on immune function: lessons learned from genome-wide analysis

REVIEW ARTICLE published: 21 April 2014 doi: 10.3389/fphys.2014.00151 Impact of vitamin D on immune function: lessons learned from genome-wide analysis Rene F. Chun 1 , Philip T. Liu 1 , Robert L. Modlin 2 , John S. Adams 1 and Martin Hewison 1* 1 Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA 2 Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA Edited by: Carsten Carlberg, University of Eastern Finland, Finland Reviewed by: Dieter Steinhilber, Goethe Universitat, Germany Mieke Verstuyf, Katholieke Universiteit Leuven, Belgium *Correspondence: Martin Hewison, Orthopedic Hospital Research Center, 615 Charles E. Young Drive South, Room 410D, Los Angeles, CA 90095-7358, USA e-mail: Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans. Keywords: macrophage, dendritic cell, intracrine, antigen-presentation, antibacterial, CYP27B1, VDR INTRODUCTION Amongst the many reported extra-skeletal effects of vitamin D, its ability to regulate immunity through effects on both the innate and adaptive systems has received considerable attention. This stems in part from homage to studies carried out more than a century ago by a then relatively unknown scientist, Dr. Nils Finsen. In 1903 Dr. Finsen won the Nobel Prize for Medicine or Physiology for showing that he could cure the epidermal form of tuberculosis (TB), lupus vulgaris, using concentrated light irradiation (Moller et al., 2005). The subsequent discovery that exposure to ultra-violet light promotes epidermal synthesis of vitamin D led to further studies describing the successful use of oral vitamin D supplementation to treat lupus vulgaris, and other mycobacterial infections such as leprosy (Airey, 1946; Herrera, 1949). The advent of antibiotic therapies for infectious diseases appeared to have consigned these studies to the history books. However, in 2006 the work of Finsen returned to center stage as a consequence of a series of genome-wide analyses that revealed pathogeninduction of an intracrine vitamin D system in monocytes (Liu et al., 2006), and an associated mechanism for anti-mycobacterial www.frontiersin.org actions of vitamin D (Wang et al., 2004), whilst also shedding light on how these responses may vary according to the vitamin D “status” of any given individual. With increasing awareness of vitamin D-deficiency across the globe (Holick, 2007), and ongoing discussions concerning the physiological and clinical relevance of this (Holick et al., 2011; Ross et al., 2011), these genome-wide analyses have played a pivotal role in defining our new perspective on non-classical vitamin D physiology. The current review will detail these developments and how they have helped to define a role for vitamin D in normal immune function. ANTIBACTERIAL RESPONSES TO VITAMIN D Despite its early use in the treatment of mycobacterial diseases such as TB and leprosy (Airey, 1946; Herrera, 1949), the immunomodulatory actions of vitamin D did not become clear until much later. Elucidation of this important non-classical action of vitamin D stemmed from two key observations. Firstly, most proliferating cells within the immune system express the nuclear receptor for active 1,25-dihydroxyvitamin D (1,25D)— the vitamin D receptor (VDR). Initial studies focused on 1,25D April 2014 | Volume 5 | Article 151 | 1 Chun et al. binding capacity in cells from the adaptive immune system such as T and B lymphocytes (T and B cells) (Bhalla et al., 1983; Provvedini et al., 1983), with subsequent reports describing specific intracellular binding of 1,25D in cells from the innate immune system such as monocytes/macrophages (Kreutz et al., 1993), dendritic cells (DC) (Brennan et al., 1987), neutrophils (Takahashi et al., 2002), and monocytic cell lines (Mangelsdorf et al., 1984). The functional significance of these data was not immediately clear but, nevertheless, it was assumed that VDRexpressing immune cells were able to respond the circulating active 1,25D in a similar fashion to classical vitamin D target tissues such as the intestine, kidney, and bone. However, this assumption was challenged by the second major observation linking vitamin D and the immunity, namely the discovery of active vitamin D metabolism by cells from the immune system. Elevated serum levels of 1,25D reported for some patients with the granulomatous disease sarcoidosis were shown to be due to conversion of pro-hormone 25D to 1,25D by tissue and systemic macrophages in these patients (Barbour et al., 1981; Adams et al., 1983). Similar observations for other inflammatory and granulomatous diseases (Kallas et al., 2010) suggested that immune activity of the enzyme that catalyzes metabolism of 25D to 1,25D, 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase) was a disease-related phenomenon. However, other studies, in vitro, highlighting the potential for macrophage 1α-hydroxylase a (...truncated)