Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation

Abstract

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

Zinc supplementation leads to immune modulation and improved survival in a juvenile model of murine sepsis

“…This effect was overcome through dietary zinc supplementation, leading to reduced severity of sepsis, as shown by amelioration of cytokine expression. 22 The existing literature, in addition to our findings, lends support to the role of zinc as an immunomodulatory agent in sepsis.…”

SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

“…In the original characterization of the mice, Hojyo et al (52) reported that hepatic zinc concentrations were ∼30% lower in Slc39a14 −/− mice compared with controls. Other studies, however, reported no alterations in hepatic zinc levels in Slc39a14 −/− mice under normal conditions (53)(54)(55). Here, we find that hepatic zinc concentrations are 11-15% lower in Slc39a14 −/− mice at 4-16 wk of age, but were not significantly different from controls at 52 wk of age [95.1 ± 2.2 μg/g (WT) vs. 92.2 μg/g (Slc39a14 −/− ), n = 4-5 per group].…”

Immune and metabolic responses in early and late sepsis during mild dietary zinc restriction

“…In septic states, serum Zn levels decline markedly and recover slowly with significant variation 3,4,41,42 . In the presence of severe deprivation of dietary Zn (1 ppm diet for 3 weeks), increased mortality and attributes of deficiency-induced immunoparalysis are observed; however, Zn levels in plasma and liver were not reported 40,41 .…”

“…In response to sepsis, trauma and hemorrhagic shock, plasma Zn levels decline while Zn accumulates in metabolically and immunologically active organs such as the liver and spleen 1–4 . Turnover of Zn within the body is also increased, reflected in sequestration in injured tissues and increased rates of disposal in the urine and stool 5–9 .…”