Vitamin D deficiency: protective against enteric infection?

VITAMIN D is critical for calcium homeostasis (4). Recently, there is renewed interest in vitamin D because of experimental evidence indicating that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D, has numerous other functions, including immunomodulatory effects (6, 10). A role in immunity was suggested by early studies showing the presence of the vitamin D receptor (VDR) in activated T cells (3). In vitro studies have shown that 1,25(OH)2D3 impedes the transcription of proinflammatory cytokines such as IL-2, IL-17, and granulocytemacrophage colony-stimulating factor (2, 18, 25), while promoting generation of Th2 cells (5). In addition, 1,25(OH)2D3 can inhibit the differentiation of dendritic cells (15, 23) and can regulate innate immunity by inducing the antimicrobial peptide cathelicidin (21). In vivo studies have shown that 1,25(OH)2D3 can at least partially protect against a number of experimental immune mediated diseases, including inflammatory bowel disease (IBD) (1,7). Evidence from mouse models [IL-10 knock out (-/-) mice, dextran sodium sulfate-treated mice and the CD45RB transfer model] indicates that vitamin D and VDR deficiency enhance the severity of IBD (7, 12, 13). In this issue of the American Journal of Physiology— Gastrointestinal and Liver Physiology, Ryz et al. (24) confirm that 1,25(OH)2D3 protects the GI tract during dextran sodium sulfate (DSS)-induced colitis. However, they also report immunosuppressive actions of 1,25(OH)2D3 that impair host defenses against colitis induced by Citrobacter rodentium. 1,25(OH)2D3-treated mice infected with C. rodentium were shown to have increased pathogen burdens and exaggerated mucosal damage (24). 1,25(OH)2D3 suppressed colonic IFN , IL-17A, and IL-6, and it reduced expression of the antimicrobial peptide RegIII (24). An important aspect of this study is the emphasis on the complexity of IL-17 biology and 1,25(OH)2D3 interaction. Although considerable literature indicates a pathological role of IL-17 in inflammatory diseases, this cytokine can also play a protective role against infections (14, 20). Thus, because of the seemingly paradoxical effects of IL-17, the authors demonstrate that inhibition of IL-17 by 1,25(OH)2D3 may not always be beneficial and can result in impaired host defense, at least in response to C. rodentium. Previous studies have also suggested a protective role of IL-17 against C. rodentium in mucoepithelial infection (17). Ishigame et al. (17), using IL-17A and IL-17F knockout (-/-) mice, showed that both IL-17A and IL-17F are required for protection of the colon against infection by C. rodentium (17). Expression of IL-17A and IL-17F was found to be essential for the induction of antimicrobial peptides -defensin 1, 3, and 4. This study demonstrated differential cell-type-specific contributions of IL-17A and IL-17F in protection against C. rodentium infection (17). Although there was a trend for reduced expression of IL-17F, in the study of Ryz et al. (24), increased host susceptibility to C. rodentium was associated with a preferential suppression of IL-17A by 1,25(OH)2D3. In addition to C. rodentium, IL-17 has been reported to mediate host defense against a number of other bacterial, fungal, and viral infections (20, 28, 29). For example, in response to the oral pathogen Porphyromonas gingivalis, IL-17RA-/mice show enhanced periodontal bone destruction, reduced serum chemokine levels, and reduced neutrophil migration to bone (29). These findings suggest that the positive influence of IL-17 on neutrophil regulation outweighs the bone destructive action of IL-17. In a respiratory infection model using Klebsiella pneumoniae, IL-17R-/mice had greater dissemination of K. pneumoniae in association with decreased neutrophil recruitment (28). It has been suggested that IL-17 can enhance host defense in lung epithelial cells by induction of chemokines and antimicrobial peptides, as well as by neutrophil regulation (19, 20, 28). It will be important to determine the effect of 1,25(OH)2D3 (which has antimicrobial activity, as well as suppressive effects on IL-17; see Refs. 16, 18, 21) in response to other infections. It is, indeed, possible that the response to 1,25(OH)2D3 will be dependent on the triggering stimuli and, at least in part, on whether the protective Th17 response outweighs the detrimental signals of IL-17. In the study by Ryz et al. (24), the authors speculate that vitamin D insufficiency may put individuals at greater risk of immune mediated disease, while making them more resistant to enteric infection. It should be noted, however, that in experimental autoimmune diseases, as well as in response to infection, the role of vitamin D is quite complex, and the results of VDR deficiency are mixed. Although in mouse models of IBD, vitamin D and VDR deficiency enhances disease severity (7, 12, 13), in VDR-/mice, experimental autoimmune encephalomyelitis (EAE) (a model of multiple sclerosis) is less severe and the onset is delayed (7, 22, 26). Thus, although 1,25(OH)2D3 suppresses EAE, studies in VDR-/mice indicate that VDR is needed for development of immune elements involved in the induction of EAE. It should also be noted that in EAE, systemic lupus erythematosus, and IBD (IL-10-/mouse model), dietary calcium is required for the suppressive effects of 1,25(OH)2 D3 on autoimmune responses (8, 11). Dietary calcium, independent of 1,25(OH)2D3, can suppress IBD in the IL-10-/mouse (9), and hypercalcemia itself has been suggested to be a mediator of the protective effect of 1,25(OH)2D3 in EAE (26). With regard to enteric infection, although the findings of Ryz et al. (24) suggest that vitamin D insufficiency results in protection against C. rodentium, this effect may not be observed with other infections. VDR deficiency in Salmonella infection, for example, results in more severe intestinal inflammation and VDR / mice are relatively more resistant than the VDR-/mice (27). Address for reprint requests and other correspondence: S. Christakos, Dept. of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103 (e-mail: [email protected]). Am J Physiol Gastrointest Liver Physiol 303: G1297–G1298, 2012; First published November 7, 2012; doi:10.1152/ajpgi.00405.2012. Editorial Focus