Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major.

We have previously reported that 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃) can selectively suppress key functions of interferon-gamma (IFN-γ) activated macrophages. To further explore this mechanism for its relevance in vivo, we investigated an infection model that crucially depends on the function of IFN-γ activated macrophages, the infection with the intracellular protozoan Leishmania major, 1α,25(OH)₂D₃ treatment of L. major infected macrophages demonstrated a vitamin D receptor (Vdr) dependent inhibition of macrophage killing activity. Further analysis showed that this was a result of decreased production of nitric oxide by 1α,25(OH)₂D₃-treated macrophages due to Vdr-dependent up-regulation of arginase 1 expression, which overrides NO production by Nos2. When analyzing the course of infection in vivo, we found that Vdr-knockout (Vdr-KO) mice were more resistant to L. major infection than their wild-type littermates. This result is in agreement with an inhibitory influence of 1α,25(OH)₂D₃ on the macrophage mediated host defense. Further investigation showed that Vdr-KO mice developed an unaltered T helper cell type 1 (Thl) response on infection as indicated by normal production of IFN-γ by CD4⁺ and CD8⁺ T cells. Therefore, we propose that the absence of 1α,25(OH)₂D₃-mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection. [ABSTRACT FROM AUTHOR]