Zinc Dyshomeostasis during Polymicrobial Sepsis in Mice Involves Zinc 1 Transporter Zip14 and Can Be Overcome by Zinc Supplementation 2 3 Corresponding Author

36 Integrity of the immune system is particularly dependent on the availability of zinc. 37 Recent data suggest that zinc is involved in the development of sepsis, a life 38 threatening systemic inflammation with high death rates, but with limited therapeutic 39 options. Altered cell zinc transport mechanisms could contribute to the inflammatory 40 effects of sepsis. In this regard, Zip14, a zinc importer induced by pro-inflammatory 41 stimuli, could influence zinc metabolism during sepsis and serve as a target for therapy. 42 Using cecal ligation and puncture (CLP) to model polymicrobial sepsis, we narrowed the 43 function of ZIP14 in regulating zinc homeostasis to hepatocytes, while hepatic 44 leukocytes were mostly responsible for driving inflammation expressing higher IL-1β, 45 TNFα, S100A8 and MMP-8. Using Zip14 knockout (KO) mice as a novel approach, we 46 found that ablation of Zip14 produced a delay in development of leukocytosis, prevented 47 liver zinc accumulation, altered the kinetics of hypozincemia and drastically increased 48 serum IL-6, TNFα, and IL-10 concentrations following CLP. Hence this model revealed 49 that the zinc transporter ZIP14 is a component of the pathway for zinc redistribution that 50 contributes to zinc dyshomeostasis during polymicrobial sepsis. In contrast, using the 51 identical CLP model, supplemental dietary zinc reduced sepsis severity as cytokines, 52 calprotectins, and blood bacterial loads were ameliorated. We conclude that the zinc 53 transporter ZIP14 influences aspects of the pathophysiology of nonlethal polymicrobial 54 murine sepsis induced by CLP through zinc delivery. The results are promising for the 55 use of zinc and its transporters as targets for future sepsis therapy. 56