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Review
, 16 (7), 705-43

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

Affiliations
Review

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

Zhi Huang et al. Antioxid Redox Signal.

Abstract

Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes. Se deficiency has long been recognized to negatively impact immune cells during activation, differentiation, and proliferation. This is related to increased oxidative stress, but additional functions such as protein folding and calcium flux may also be impaired in immune cells under Se deficient conditions. Supplementing diets with above-adequate levels of Se can also impinge on immune cell function, with some types of inflammation and immunity particularly affected and sexually dimorphic effects of Se levels in some cases. In this comprehensive article, the roles of Se and individual selenoproteins in regulating immune cell signaling and function are discussed. Particular emphasis is given to how Se and selenoproteins are linked to redox signaling, oxidative burst, calcium flux, and the subsequent effector functions of immune cells. Data obtained from cell culture and animal models are reviewed and compared with those involving human physiology and pathophysiology, including the effects of Se levels on inflammatory or immune-related diseases including anti-viral immunity, autoimmunity, sepsis, allergic asthma, and chronic inflammatory disorders. Finally, the benefits and potential adverse effects of intervention with Se supplementation for various inflammatory or immune disorders are discussed.

Figures

FIG. 1.
FIG. 1.
Selenoprotein synthesis. The process is initiated by the charging of serine (Ser) onto a dedicated tRNA (tRNA[ser]Sec) to generate Ser-tRNASec. The seryl residue of Ser-tRNASec is enzymatically phosphorylated, and then is converted to Sec-tRNASec using monoselenophosphate as a donor of Se. The Sec-tRNASec is used to transfer Sec into nascent selenoproteins co-translationally through a mechanism that requires several dedicated cis elements present in the selenoprotein mRNA (SECIS element) and protein factors that act in trans including SBP2 and EFsec and others. This results in recoding UGA from a stop codon to a Sec-insertion codon and the resulting protein contains the Sec amino acid, which is utilized by selenoproteins for various biological processes. Sec-tRNASec, selenocysteyl-tRNASec; Se, selenium; SBP2, SECIS-binding protein 2; SECIS, selenocysteine insertion sequence; EFSec, selenocysteine-specific translation elongation factor.
FIG. 2.
FIG. 2.
Comparison of the selenoprotein transcriptome in human and mouse T cells. Total RNA was extracted from T cells from a normal healthy volunteer and real-time polymerase chain reaction was performed with primers as previously described (240). Levels of each mRNA were normalized to the housekeeping mRNA, ubiquitin c, and the relative abundance compared with published results for mouse T cells (36). Results show some similarities between human and mouse T cells, with the most abundant mRNAs common to both species. One exception to this is SelP, which is much higher in relative abundance in mouse T cells compared with humans.
FIG. 3.
FIG. 3.
The relationship between different reactive oxygen species (ROS). The two major subsets, free radicals and nonradical derivatives, are shown with illustrations showing how members of each are related to each other. There are several sources of superoxide (·O2−), which can subsequently be converted to other ROS such as hydrogen peroxide (H2O2) and peroxynitrite (ONOO-).
FIG. 4.
FIG. 4.
Generation of superoxide by NADPH oxidase. On activation (e.g., LPS in phagocytes or TCR in T cells), the cytosolic components including p47phox, p67phox, and p40phox, assemble at the membrane to form the enzyme complex. An electron is transferred through the catalytic core (b558) comprised of two subunits, gp91phox (NOX2) and p22 phox. In resting cells, GDP-bound RAC is in complex with its inhibitor GDI, and on activation, GTP is exchanged for GDP via guanine nucleotide exchange factor (GEF) and this causes RAC to interact with membrane-associated p47phox. This GTP-bound form of RAC positively regulates the actions of the NOX2 complex, and the result is the transfer of one electron to oxygen to generate superoxide. This superoxide can subsequently be converted by SOD to diffusable H2O2. NADPH, nicotinamide adenine dinucleotide phosphate; LPS, lipopolysaccharide; TCR, T cell receptor; PHOX, phagocytic oxidase; NOX, NADPH oxidase; RAC, Ras-related C3 botulinum toxin substrate; GDI, GDP dissociation inhibitor; SOD, superoxide dismutase.
FIG. 5.
FIG. 5.
Two alternative models for the actions of H2O2 as a secondary messenger. The conventional model (top) involves direct actions of H2O2 on adjacent Cys residues within a signaling molecule to form a disulfide bond that alters conformation of the active site and the activation state. A new model (bottom) has been proposed in which peroxidases such as GPx1 promote the oxidation of adjacent Cys residues and formation of disulfide bonds. In this sense, the actions of H2O2 are indirect and the direct affects are determined by levels and locations of GPX1 and GSH. Cys, cysteine; GSH, glutathione; GPX, glutathione peroxidase.
FIG. 6.
FIG. 6.
The basic steps involved in store-operated Ca2+ release (SOCE) for either T cells or macrophages. Stores of Ca2+ for these cells are largely maintained in ER. Engagement of receptors on the surface of immune cells leads to activation of PLCγ, which converts PIP3 to DAG and IP3. IP3 rapidly binds to the IP3 receptor on the ER membrane, which causes loss of Ca2+ from the ER stores. The lower [Ca2+] in the ER lumen is sensed by EF-hand motifs in the ER luminal STIM1 molecule, and this leads to oligomerization of STIM1. Oligomerized STIM1 physically interacts with Orai1 on the plasma membrane, which activates this channel and causes the entry of high levels of Ca2+. ER, endoplasmic reticulum; PLCγ, phospholipase Cγ; IP3; inositol-1,4, 5-trisphosphate; DAG, diacylglycerol; EF, elongation factor; STIM1, stromal interaction molecule 1.
FIG. 7.
FIG. 7.
Two different NADPH oxidase systems operate during activation of T cells. At early stages after TCR-activation, Ca2+-dependent IP3 generation leads to activation of the IP3 receptor on the ER membrane. This causes DUOX1-induced superoxide, which is dismutated into H2O2. This acts to promote T cell activation in the early stages. DUOX isoforms may also operate within the endosome. At later stages, the NOX2-based system generates superoxide in a Ca2+-independent manner. H2O2 generated from these steps may build up and negatively regulate the IP3 pathway through inhibition of SHP-2. This is believed to down-modulate T cell activation. DUOX, dual oxidase; SHP-2.
FIG. 8.
FIG. 8.
Activation signals in naive T cells during TCR-stimulation are enhanced by higher levels of dietary Se. Within seconds Ca2+, flux is triggered by TCR-stimulation, and this is enhanced by increasing dietary Se. In addition, later signals including oxidative burst and NFAT activation and translocation are enhanced by higher Se intake. These signals lead to induced IL-2 and IFN-γ gene expression, which are also increased with higher Se intake. The mechanisms by which Se levels affect these signaling events involves the content of higher free thiols, although specific alterations in specific disulfide bonds in signaling molecules have not yet been identified. NFAT, nuclear factor of activated T cells; IL-2, interleukin 2; IFN-γ, interferon-γ.
FIG. 9.
FIG. 9.
Selk cleavage by m-calpain in macrophages. In resting macrophages, Selk synthesized on the ribosome is immediately cleaved by activated m-calpain. This results in nearly all Selk existing as inactived protein in resting macrophages as demonstrated by lower Ca2+ flux and migration in response to chemokines such as MCP-1. TLR-activation increases expression of calpastatin, which inhibits cleavage by m-calpain and results in higher levels of full-length Selk. Thus, in activated macrophages, full-length Selk is able to efficiently promote Ca2+ and migration toward chemokines. MCP-1, monocyte chemotactic protein-1; TLR, Toll-like receptor.
FIG. 10.
FIG. 10.
Effects of Se intake on CD4+ T cell differentiation. Adequate levels of Se intake do not bias T cell differentiation and T helper (Th) 1 versus Th2 differentiation is largely determined by signals provided by the antigen-presenting cell or cytokine milleau. For example, CD4+ T cells activated in a pro-Th1 environment or a pro-Th2 environment can differentiate into either Th1 or Th2 cells. Se supplementation boosts TCR signals and skews differentiation toward a Th1 phenotype. In contrast, Se deficiency leads to low TCR signals and skews differentiation toward lowered activation states with a biase toward a Th2 phenotype.
FIG. 11.
FIG. 11.
Analyses of cell markers during activation of naive CD4+ T cells from mice fed different Se diets. Under conditions previously described (102), purified splenic CD4+ T cells were stimulated for 18 h through the TCR, and flow cytometry was used to measure markers for Th1 cells (CD40L), Treg cells (CD25 and FoxP3), and a marker excluded from Treg cells (RANKL). Preliminary studies in our laboratory suggest that increased Se intake leads to higher levels of Th1 and Treg markers. FoxP3, forkhead box P3; RANKL, receptor activator for nuclear factor-κB ligand.
FIG. 12.
FIG. 12.
Hypothetical effect of higher Se intake on chromatin remodeling. Evidence suggests that higher levels of dietary Se may affect epigenetic states of certain gene regions, and this may be an important factor in how Se levels influences T helper cell differentiation. This may occur by increasing levels of redox intermediates in the nucleus such as free thiols on signaling molecules or reduced Txn-1, which may influence the rate-limiting steps of enzymes involved in chromatin remodeling. This can lead a poised state of chromatin that is able to more quickly respond to TCR-stimulation and rapidly generate mRNA for master regulator proteins such as T-bet. Txn-1, thioredoxin 1; T-bet, T-box expressed in T cells.
FIG. 13.
FIG. 13.
Selenoproteins in the ER regulate inflammation in part through effects on protein-folding. Evidence has been presented for roles for SelS and Selk in regulating ER stress. SelM and Sep15 have been suggested to play key roles in protein folding. Altogether, low Se intake may lead to low expression of these selenoproteins. Decreased expression of some or all of these selenoproteins may cause an increase in misfolded proteins and cause ER stress. This may lead to secretion of proinflammatory mediators by affected cells and eventually increased inflammation.
FIG. 14.
FIG. 14.
Cyclical decrease in Se status under conditions of sepsis or other types of inflammation. Initiated by sepsis or circulating LPS, inflammatory cytokines cause down-regulation of SelP biosynthesis, which leads to decreased delivery of Se to tissues, which can further promote inflammation as described in Figure 13. In addition, inflammation can cause increased vascular permability in certain tissues, which also can contribute to possible loss of Se from circulation and exacerbate inflammation. Intervention with Se supplementation may attenuate conditions involved in this cycle by increasing overall Se in circulation and inhibiting ER stress or other oxidative stress conditions, thus leading to an overall decreased inflammatory response.
FIG. 15.
FIG. 15.
Results from mouse models of allergic asthma suggest that dietary Se levels may alter disease outcome. In relationship to the affects of dietary Se on T helper cell differentiation as outlined in Figure 10, low Se status leads to an overall lower immune response to Th2-inducing allergens. Increasing Se status to adequate levels increases TCR signal strength and enables stronger Th2 responses that drive allergic asthma. Further increasing Se status with Se supplementation further increases TCR signal strength, but skews CD4+ T cell away from Th2-type that drives allergic asthma.

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