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Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function

Abstract

Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.

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Figure 1: Decrease in intracellular free zinc in DCs after LPS treatment.
Figure 2: Intracellular zinc depletion mimics and zinc supplementation blocks LPS-induced DC maturation.
Figure 3: Intracellular trafficking and endocytosis of MHC class II are blocked by TPEN treatment.
Figure 4: LPS-induced alterations in zinc transporter expression depend on TRIF.
Figure 5: Zip6 overexpression blocks LPS-induced reduction in intracellular free zinc and upregulation of surface MHC class II.
Figure 6: LPS treatment reduces intracellular free zinc and alters expression of zinc transporters in splenic CD11c+ cells in vivo.

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Acknowledgements

We thank K. Takatsu (University of Tokyo, Tokyo, Japan) for P25 TCR–transgenic mice; T. Saito (RIKEN RCAI, Yokohama, Japan) for Phoenix cells; T. Sudo (Toray, Kamakura, Japan) for CHO cells producing granulocyte-macrophage colony-stimulating factor; T. Mitchell (University of Louisville, Louisville, Kentucky) for the pMSCV-IRES-Thy1.1 retroviral vector; O. Ohara (DNA Kazusa, Kazusa and RIKEN RCAI, Yokohama, Japan) for mouse Zip6 cDNA; A. Ito, T. Yamasaki, E. Iketani and T. Hayashi for technical assistance; and R. Masuda and M. Shimura for secretarial assistance. Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (S.Y., M.M. and T.H.), the Uehara Foundation (M.M.) and the Osaka Foundation for the Promotion of Clinical Immunology (M.M. and T.H.).

Author information

Authors and Affiliations

Authors

Contributions

H.K. and H.M. did most of the experiments; H.K. helped with retrovirus infection and did experiments using T cells; M.I. helped with the quantitative PCR; S.H. helped with the flow cytometry; T.F. and S.Y. provided advice for the experiments and manuscript; T.K. and S.A. provided knockout mice and some reagents and advice for the experiments and manuscript; and M.M. and T.H. designed all the experiments and prepared the manuscript.

Corresponding author

Correspondence to Toshio Hirano.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

TPEN increased surface expression of MHCII and MHCI but not that of CD40 and CD80 molecules in DCs. (PDF 69 kb)

Supplementary Fig. 2

TPEN treatment, which decreased intracellular zinc did not alter expression of H2-Ab1 or Cd86 mRNA and did not induce cytokine expression in DCs. (PDF 83 kb)

Supplementary Fig. 3

Effect of TPEN on DC maturation was not due to contaminating endotoxin. (PDF 100 kb)

Supplementary Fig. 4

Zinc ion plus zinc pyrithione but not zinc ion or zinc pyrithione alone inhibited LPS-induced decrease of free zinc in DCs. (PDF 86 kb)

Supplementary Fig. 5

LPS and polyIC but not R-848 and CpG treatment decreased intracellular zinc level in DCs. (PDF 48 kb)

Supplementary Fig. 6

TPEN injection increased surface expression of MHCII molecules on DCs. (PDF 27 kb)

Supplementary Fig. 7

Zinc plus pyrithione treatment inhibited R-848- and CpG-induced upregulation of MHCII and CD86 in DCs. (PDF 30 kb)

Supplementary Fig. 8

Specificity of anti-Zip6 polyclonal antibody. (PDF 245 kb)

Supplementary Table 1

PCR primers. (PDF 17 kb)

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Kitamura, H., Morikawa, H., Kamon, H. et al. Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7, 971–977 (2006). https://doi.org/10.1038/ni1373

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