Induction of the metal transporter ZIP8 by interferon gamma in intestinal epithelial cells: Potential role of metal dyshomeostasis in Crohn's disease
Introduction
In the intestinal microenvironment, transition metals are required for intestinal homeostasis and used as a nutrient source by the resident microbiota. Interest in metal homeostasis in intestinal disease has been spurred by an exome sequencing study of Crohn's disease (CD) patients that identified a single nucleotide polymorphism (SNP) in SLC39A8 (rs13107325; ZIP8 A391T) associated with an increased risk of CD [1]. The SNP ranks in the top 10 most frequently identified SNPs in genome-wide association studies; the major allele is associated with hypertension and Parkinson's disease, while the minor allele is associated obesity, dyslipidemia, schizophrenia, and CD [2]. The mechanisms underlying these pleiotropic associations are unknown.
SLC39A8 encodes the plasma membrane protein ZIP8. ZIP proteins are best characterized as zinc influx transporters, although ZIP8 has been shown to transport multiple divalent cations, including zinc [3] and manganese [4,5]. SLC39A8 is induced by inflammatory stimuli in multiple cell types [[6], [7], [8]]. Acute induction of ZIP8 restrains NF-κB signaling by zinc binding of IKKβ to inhibit nuclear translocation [7], while chronic ZIP8 induction and increased intracellular zinc drives metallothionein expression to promote tissue destruction [8]. ZIP8-mediated manganese transport is critical for the activity of two manganese-dependent enzymes, arginase and β-1,4-galactosyltransferase [9], but less is known about the role of ZIP8-mediated manganese transport in inflammation. This foundation of known ZIP8 biology engenders hypotheses that perturbation of the constitutive and induced activities of ZIP8 by disease-associated genetic variation contribute to CD pathogenesis, and that better understanding of metal homeostasis in the gut may offer new approaches to diagnosis and treatment. Our results represent the first characterization of ZIP8 in the gut and CD.
Section snippets
Secondary data analysis
We analyzed publicly-available RNAseq data derived from ileal biopsies from newly diagnosed CD patients [10]. Co-expression analyses were performed in Excel (Microsoft) and Prism 8.0 (Graphpad).
Human specimens
Formalin-fixed, paraffin-embedded human ileal sections were obtained with patient consent and Johns Hopkins Hospital (JHH) institutional review board approval (NA_00038329). Human enteroids (3D spheroids) were prepared from biopsies taken at ileocolonoscopy from three healthy subjects with patient
SLC39A8 expression is increased in active ileal CD and expression correlates with inflammatory cytokine expression
Initially, we examined whether SLC39A8 is differentially expressed in active CD. Comparing transcriptional data from ileal biopsies from patients with CD versus controls [10], SLC39A8 was differentially expressed in patients with CD with the highest expression in the most severe inflammatory disease (Fig. 1a). The relative increase in expression paralleled CD severity (p-trend < 0.0001). There was significant inter-individual variation in SLC39A8 (coefficient of variation in most severe disease
Discussion
In this work, we found that SLC39A8 mRNA expression is increased in active CD. There is high inter-individual variation in SLC39A8 expression in severe disease compared to controls. This observation is in line with our previous study in which we showed that IBD-associated risk genes with the lowest variance in expression in controls demonstrated the highest variance in CD patients [19]. We hypothesized that IBD-associated risk genes are tightly regulated to maintain intestinal homeostasis in
Funding
This work was supported by the NIH/NIDDK Johns Hopkins Conte Gastrointestinal Core Center (P30 DK-089502); Johns Hopkins University School of Medicine Clinician Scientist Career Development Award; and the Ludwig-Bayless Discovery Award to J. Melia.
Acknowledgements
We wish to acknowledge Ms. Karen Fox-Talbot (Johns Hopkins Oncology Tissue Services), Dr. Nicholas Zachos, and Mr. George McNamara of the Hopkins Digestive Diseases Basic and Translational Research Core (P30 DK-089502).
References (27)
- et al.
A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition
Gastroenterology
(2016) - et al.
SLC39A8 deficiency: a disorder of manganese transport and glycosylation
Am. J. Hum. Genet.
(2015) - et al.
Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8
Am. J. Hum. Genet.
(2015) - et al.
ZIP8 regulates host defense through zinc-mediated inhibition of NF-kappaB
Cell Rep.
(2013) - et al.
Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis
Cell
(2014) - et al.
Inhibitory effect of divalent metal cations on zinc uptake via mouse Zrt-/Irt-like protein 8 (ZIP8)
Life Sci.
(2017) - et al.
ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading
J. Biol. Chem.
(2012) - et al.
Cd2+ versus Zn2+ uptake by the ZIP8 HCO3--dependent symporter: kinetics, electrogenicity and trafficking
Biochem. Biophys. Res. Commun.
(2008) - et al.
Detection and interpretation of shared genetic influences on 42 human traits
Nat. Genet.
(2016) - et al.
Mammalian zinc transporters: nutritional and physiologic regulation
Annu. Rev. Nutr.
(2009)
The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia
Am. J. Physiol. Lung Cell Mol. Physiol.
Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity
J. Clin. Investig.
Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature
J. Clin. Investig.
Cited by (19)
Influences of five dietary manganese sources on growth, feed utilization, lipid metabolism, antioxidant capacity, inflammatory response and endoplasmic reticulum stress in yellow catfish intestine
2023, AquacultureCitation Excerpt :DMT1 could transport Mn across the microvillus into the enterocytes in the intestine (Trinder et al., 2000; Hansen et al., 2009). ZIP8 expression was predominant in intestinal epithelial cells and lamina propria immune cells, and transport extracellular manganese ions into cells (Melia et al., 2019; Lv et al., 2022). ZIP14 expression was predominant in the intestine and localized in the basolateral membrane of enterocytes (Scheiber et al., 2019).
Manganese transport in mammals by zinc transporter family proteins, ZNT and ZIP
2022, Journal of Pharmacological SciencesCitation Excerpt :The expression of ZIP8 is markedly increased by IL-1β treatment.91 The expression of ZIP8 mRNA is also induced by IFN-γ.92 In contrast, the expression of ZIP8 is suppressed by GSH and Cd exposure through the downregulation of Sp1.93
Zinc transporters and their functional integration in mammalian cells
2021, Journal of Biological ChemistryCitation Excerpt :For example, rare polymorphic variants impair ZIP4 cleavage, resulting in AE (72). An alanine-to-threonine change at position 391 of ZIP8 resulting from a nonsynonymous SNP (rs13107325C→T) in SLC39A8 is associated with a variety of diseases including Crohn's disease (242, 243), severe idiopathic scoliosis (244), and circulating lipid levels and risk of coronary artery disease (245). Moreover, aberrant expressions of human zinc transporters are pathogenic.
Type I Interferons Ameliorate Zinc Intoxication of Candida glabrata by Macrophages and Promote Fungal Immune Evasion
2020, iScienceCitation Excerpt :For example, IFN-I responses reduce plasma Zn concentrations by inducing hepatic metallothionein expression in various model organisms (Guevara-Ortiz et al., 2005; Van Miert et al., 1990; Morris and Huang, 1987; Sato et al., 1996), as well as in human cells (Friedman and Stark, 1985; Nagamine et al., 2005; Read et al., 2017). IFN-γ regulates plasma Zn concentrations (Morimoto et al., 1987), Zn transporter expression in intestinal epithelial cells and pancreatic β-cells (Egefjord et al., 2009; Melia et al., 2019), as well as Zn levels in mycobacteria-containing vacuoles (Wagner et al., 2005a). In contrast, IFN-λ3 increases intracellular Zn levels (Read et al., 2017).
Effects of Long-Term Dietary Zinc Oxide Nanoparticle on Liver Function, Deposition, and Absorption of Trace Minerals in Intrauterine Growth Retardation Pigs
2023, Biological Trace Element Research