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ZIP8 regulates host defense through zinc-mediated inhibition of NF-?B.

ABSTRACT: Activation of the transcription factor NF-?B is essential for innate immune function and requires strict regulation. The micronutrient zinc modulates proper host defense, and zinc deficiency is associated with elevated inflammation and worse outcomes in response to bacterial infection and sepsis. Previous studies suggest that zinc may regulate NF-?B activity during innate immune activation, but a mechanistic basis to support this has been lacking. Herein, we report that the zinc transporter SLC39A8 (ZIP8) is a transcriptional target of NF-?B and functions to negatively regulate proinflammatory responses through zinc-mediated down-modulation of I?B kinase (IKK) activity in vitro. Accordingly, fetal fibroblasts obtained from Slc39a8 hypomorphic mice exhibited dysregulated zinc uptake and increased NF-?B activation. Consistent with this, mice provided zinc-deficient dietary intakes developed excessive inflammation to polymicrobial sepsis in conjunction with insufficient control of IKK. Our findings identify a negative feedback loop that directly regulates innate immune function through coordination of zinc metabolism.

SUBMITTER: Liu MJ

PROVIDER: S-EPMC3615478 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB.

Liu Ming-Jie MJ Bao Shengying S Gálvez-Peralta Marina M Pyle Charlie J CJ Rudawsky Andrew C AC Pavlovicz Ryan E RE Killilea David W DW Li Chenglong C Nebert Daniel W DW Wewers Mark D MD Knoell Daren L DL

Cell reports 20130209 2

Activation of the transcription factor NF-κB is essential for innate immune function and requires strict regulation. The micronutrient zinc modulates proper host defense, and zinc deficiency is associated with elevated inflammation and worse outcomes in response to bacterial infection and sepsis. Previous studies suggest that zinc may regulate NF-κB activity during innate immune activation, but a mechanistic basis to support this has been lacking. Herein, we report that the zinc transporter SLC3 ...[more]

PMID: 23403290

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Project description:Manganese (Mn) and Zinc (Zn) are essential micronutrients whose concentration and location within cells are tightly regulated at the onset of infection. Two families of Zn transporters (ZIPs and ZnTs) are largely responsible for regulation of cytosolic Zn levels and to a certain extent, Mn levels, although much less is known regarding Mn. The capacity of pathogens to persevere also depends on access to micronutrients, yet a fundamental gap in knowledge remains regarding the importance of metal exchange at the host interface, often referred to as nutritional immunity. ZIP8, one of 14 ZIPs, is a pivotal importer of both Zn and Mn, yet much remains to be known. Dietary Zn deficiency is common and commonly occurring polymorphic variants of ZIP8 that decrease cellular metal uptake (Zn and Mn), are associated with increased susceptibility to infection. Strikingly, ZIP8 is the only Zn transporter that is highly induced following bacterial exposure in key immune cells involved with host defense against leading pathogens. We postulate that mobilization of Zn and Mn into key cells orchestrates the innate immune response through regulation of fundamental defense mechanisms that include phagocytosis, signal transduction, and production of soluble host defense factors including cytokines and chemokines. New evidence also suggests that host metal uptake may have long-term consequences by influencing the adaptive immune response. Given that activation of ZIP8 expression by pathogens has been shown to influence parenchymal, myeloid, and lymphoid cells, the impact applies to all mucosal surfaces and tissue compartments that are vulnerable to infection. We also predict that perturbations in metal homeostasis, either genetic- or dietary-induced, has the potential to impact bacterial communities in the host thereby adversely impacting microbiome composition. This review will focus on Zn and Mn transport via ZIP8, and how this vital metal transporter serves as a "go to" conductor of metal uptake that bolsters host defense against pathogens. We will also leverage past studies to underscore areas for future research to better understand the Zn-, Mn- and ZIP8-dependent host response to infection to foster new micronutrient-based intervention strategies to improve our ability to prevent or treat commonly occurring infectious disease.

Dataset Information

ZIP8 regulates host defense through zinc-mediated inhibition of NF-?B.

Publications

ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB.

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