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Published online before print June 5, 2007 as doi: 10.1096/fj.06-7261com.

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

Jan Ehrchen, Laura Helming, Georg Varga, Bastian Pasche, Karin Loser, Matthias Gunzer, Cord Sunderkötter, Clemens Sorg, Johannes Roth, and Andreas Lengeling

E-mail contact: andreas.lengeling@helmholtz-hzi.de

We have previously reported that 1{alpha},25-dihydroxyvitamin D3 (1{alpha},25(OH)2D3) can selectively suppress key functions of interferon-gamma (IFN-{gamma}) 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-{gamma} activated macrophages, the infection with the intracellular protozoan Leishmania major. 1{alpha},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 1{alpha},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 1{alpha},25(OH)2D3 on the macrophage mediated host defense. Further investigation showed that Vdr-KO mice developed an unaltered T helper cell type 1 (Th1) response on infection as indicated by normal production of IFN-{gamma} by CD4+ and CD8+ T cells. Therefore, we propose that the absence of 1{alpha},25(OH)2D3-mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection.




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