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

Jan Ehrchen^*,,1, Laura Helming^,1,2, Georg Varga, Bastian Pasche, Karin Loser, Matthias Gunzer, Cord Sunderkötter^*,, Clemens Sorg^*,3, Johannes Roth^* and Andreas Lengeling^,4

^* Institute for Experimental Dermatology, University of Münster, Münster, Germany;

Research Group Infection Genetics, Department of Experimental Mouse Genetics;

Junior Research Group Immunodynamics, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany; and

Department of Dermatology, University of Münster, Münster, Germany

⁴Correspondence: Research Group Infection Genetics, Department of Experimental Mouse Genetics, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany. E-mail: andreas.lengeling{at}helmholtz-hzi.de

We have previously reported that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) can selectively suppress key functions of interferon-gamma (IFN-) 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- activated macrophages, the infection with the intracellular protozoan Leishmania major. 1,25(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 1,25(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 1,25(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- by CD4⁺ and CD8⁺ T cells. Therefore, we propose that the absence of 1,25(OH)₂D₃-mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection.

Key Words: interferon-gamma • host resistance • macrophage • knockout mice • parasite