Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major.
We have previously reported that 1alpha,25-dihydroxyvitamin D3 (1alpha,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. 1Alpha,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 1alpha,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 1alpha,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 1alpha,25(OH)2D3-mediated inhibition of macrophage microbicidal activity in Vdr-KO mice results in increased resistance to Leishmania infection.
Ehrchen
Jan
J
Institute for Experimental Dermatology, University of Münster, Münster, Germany.
Helming
Laura
L
Varga
Georg
G
Pasche
Bastian
B
Loser
Karin
K
Gunzer
Matthias
M
Sunderkötter
Cord
C
Sorg
Clemens
C
Roth
Johannes
J
Lengeling
Andreas
A
D000818:Animals; D001119:Arginase / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D004198:Disease Susceptibility; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism
D016207:Cytokines; D018167:Receptors, Calcitriol; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase; D002117:Calcitriol