Investigation of the function of Zip14-mediated transient zinc-uptake into the liver during normal infection and sepsis
Evolutionary Cell and Developmental Biology (Zoology)
Immunology
Final Report Abstract
Research of recent years made it abundantly clear that zinc is of extraordinary importance in human health and disease. Debates over zinc supplementation to support the immune system during infections and other diseases continue. Recent data suggest that zinc is involved in the development of sepsis, a life threatening systemic inflammation with increasing incidence, high death rates, but limited therapeutic options. During inflammation, zinc is transferred to the liver causing serum hypozincemia. Using cecal ligation and puncture (CLP) as a well-accepted model for polymicrobial sepsis, we showed that compared to LPS-induced inflammation, not only the increase in hepatic zinc was significantly stronger during sepsis, but also the decrease of zinc in the serum was more pronounced, directly correlating with a sharp increase in blood immune cells. In addition, expression of zinc transporters, zinc binding and zinc regulated genes expression was altered. A possible connection of this to higher serum levels of inflammatory and anti-microbial markers remains to be proven. As Zip14 turned out to be majorly responsible for the impressive and fast zinc redistribution during sepsis, Zip14KO mice were used to investigate the teleology behind this phenomenon. Results suggest that zinc-transfer to the hepatocytes is essential for the generation of acute phase proteins, but also supports proliferation of hepatocytes. In addition, Zip14-mediated zinc uptake into hepatocytes protected the liver from apoptosis and sepsis-induced failure. Expression of other zinc importers and zinc binding proteins was increased, but were not sufficient to compensate for the lack of Zp14. Instead of the quick fall in serum zinc and slow normalization observed in septic WT mice, a fluctuation of serum zinc was observed in KO mice. This disturbed zinc homeostasis lead to a failure in resolution of the inflammation as seen by constantly high levels of the pro-inflammatory mediators IL-6 and TNFα. Zinc has been suggested to be beneficial for treatment of sepsis; however, experimental evidence has been conflicting. For this project, 7 day dietary supplementation of mice with zinc prior to the induction of polymicrobial sepsis was chosen. Supplemental dietary zinc prevented CLP- induced hypozincemia. Results revealed an overall very positive effect of zinc supplementation: activity of mice was higher, hyper-inflammation was ameliorated, liver proliferation was improved, bile production was normalized, and liver damage was decreased. Surprisingly, even though the amount of anti-microbial factors in the blood was decreased, bacterial loads in blood and spleen were lower in the supplemented compared to the zinc adequate mice. This suggests that the main purpose of zinc redistribution is not to withhold zinc from microorganisms. Our results did not only answer open questions on the mechanisms and teleology of zinc redistribution during acute phase response compared to sepsis. They point to a benefit of using zinc for therapy of sepsis and other inflammatory diseases. Supplementation of individuals with zinc prior to major surgery may act as the prevention of unbalanced zinc-homeostasis and improve immune response and should tested in clinical studies. Benefits of zinc for established disease remain to be tested. Supplementation with or shortly after disease induction should be approached very carefully in the future to not cause total immune suppression. Experiments investigating more time-points, doses and application routes are already planned.
Publications
- Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation. APS Gastrointestinal and Liver Physiology, Vol 309 Issue 9, November 2015, Pages G768-G778
Wessels, I., Cousins, C.
(See online at https://doi.org/10.1152/ajpgi.00179.2015)
