I. Introduction
Selenium (Se) is an essential micronutrient that is important for various aspects of human health, including proper thyroid hormone metabolism, cardiovascular health, prevention of neurodegeneration and cancer, and optimal immune responses. Very low (deplete) or very high (toxic) levels of Se intake can be detrimental or possibly fatal.
The biological effects of Se are mainly exerted through its incorporation into selenoproteins, and selenoproteins are involved in the activation, proliferation, and differentiation of cells that drive innate and adaptive immune responses. Dietary Se and selenoproteins are not only important for initiating or enhancing immunity, but they are also involved in immunoregulation, which is crucial for preventing excessive responses that may lead to autoimmunity or chronic inflammation.
II. Bioactive Forms of Se and Their Effects
The major form of Se ingested by humans is selenomethionine (Se-Met), although other forms of Se are present in foods.
III. Incorporation of Dietary Se into Selenoproteins
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IV. The Selenoprotein Family
A. An overview of selenoproteins
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B. Selenoprotein functions
1. Glutathione peroxidases
The glutathione peroxidase (GPX) selenoenzymes in humans consist of eight isoforms, but only six (GPX1-6) contain Sec.
Of these four GPX enzymes, only GPX3 is secreted for circulation or for use in plasma, in extracellular spaces, or by neighboring cells. In fact, GPX3 accounts for 20%–40% of total plasma Se in humans (131).
2. Thioredoxin reductases
The thioredoxin reductase (TXNRD) enzymes are another well-characterized subfamily of selenoproteins that perform an essential redox role by regenerating reduced thioredoxin (TXN or TRX) within cells (147, 251).
3. Deiodinases
The iodothyronine deiodinase family is central for thyroid hormone regulation and consists of three enzymes: types 1, 2, and 3 (DIO1, 2, and 3) (219). (...) However, levels of active thyroid hormone may affect systemic Se available for selenoprotein sythesis in a variety of tissues, including those involved in immune responses (172). In this sense, the DIO enzymes may have important indirect roles in inflammation and immunity.
4. Selenoprotein P
Selenoprotein P (SELP or SEPP1) is unique in that it contains multiple Sec residues (up to 10 per SELP and Selp molecule in humans and rodents, respectively). SELP has been shown to play an important role in the transport of Se through the plasma to certain tissues, with the testes and brain particularly dependent on SELP for adequate Se levels (32, 101, 212). SELP is synthesized in several different tissues, but hepatically derived SELP serves as a key Se transporter. Hepatic SELP is secreted into plasma, which then influences whole-body Se homeostasis (222).
5. Selenoproteins K and S
Two selenoproteins related to inflammation and immunity include the endoplasmic reticulum (ER) transmembrane proteins, SELK and SELS. Both of these proteins have been proposed to play a role in protecting cells during conditions that lead to ER stress. For SELS, this appears to be related to its role in retrograde translocation of misfolded proteins from the ER (80).
6. Other selenoprotein family members
What defines members of the selenoprotein family is the incorporated Sec residue, but how the different selenoproteins functionally utilize Sec is quite diverse. Some biological functions include transcriptional regulation (SelH), phospholipid synthesis (SELI), protein-folding (SELM and SEP15), methionine sulfoxide reduction (SELR), and the biosynthesis of selenoproteins (SPS2). Most of these functions are necessary for proper functioning of most tissues and cell types, including those involved in immune responses. Functions for several selenoprotein family members remain unclear or unknown.
C. The hierarchy of selenoprotein expression
With moderate Se deficiency, it has been suggested that expression of nonessential selenoproteins are preferentially lost, whereas essential selenoproteins are maintained (160). In addition, under Se deficient conditions, not all tissues are equivalently supplied with the limited amounts Se (221). Tissues such as the thyroid gland and brain maintain Se levels during deficiency, and tissues such as those of the immune system exhibit a more rapid decline in bioavailable Se leading to lower selenoprotein synthesis. These concepts are often referred to as “the hierarchy of selenoprotein synthesis” and should be carefully considered when investigating the effects of low Se status on immune responses or other aspects of human health.
V. Selenoprotein Expression in Immune Tissues and Cells
A. Tissue and cellular distribution under physiological conditions
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B. Selenoprotein expression in immune cells and tissues in response to Se changes
Similar to other cell types, immune cells respond to increased dietary Se by increasing expression of many selenoproteins, although not all selenoproteins are equivalently affected. T cells from mice fed diets with increasing Se content (from 0.08 to 1.0 ppm for 8 weeks) exhibited higher Gpx1 and Txnrd1 activity (102). Similar results were obtained in human studies involving Se supplementation (50 or 100 μg/day as sodium selenite) in which both GPX1 and GPX4 activity were increased in lymphocytes from supplemented individuals compared with nonsupplemented controls (29). In a recent study involving humans receiving enriched Se diets (50–200 μg/day Se-enriched yeast or 50 g/day Se-enriched onions) or placebos, higher Se diets increased mRNA levels for SELR, SELW, and SELS in peripheral blood mononuclear cells (PBMCs) (88).
C. The selenoproteomic response during immune cell activation
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VI. Se and Redox Signaling in Immune Cells
A. An overview
The generation of ROS by immune cells is often associated with the killing of microbes by phagocytes. Indeed, ROS produced by macrophages and neutrophils is essential for the oxidative destruction of phagocytosed pathogens and fully effective immunity. ROS have also become recognized as important mediators of cell signaling and cell-to-cell communication for a variety of phagocytic and nonphagocytic immune cells. For example, mutations in genes encoding superoxide-generating enzymes can disrupt the oxidative burst generated by phagocytes, thus leading to chronic granulomatous disease (CGD) that is characterized by severe, life-threatening bacterial and fungal infections (106).
Interestingly, levels of Se intake can influence the production of ROS and their downstream effects. The next sections describe the role of redox mechanisms and how Se may affect these mechanisms.
B. Types of ROS important for immune cell signaling
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C. Se levels related to the production of ROS in immune cells
Activation of immune cells through cell surface or intracellular receptors can lead to high levels of ROS within minutes, often referred to as an oxidative burst. In general, activated phagocytes produce higher levels of ROS than nonphagocytic immune cells such as T cells.
Se levels in immune cells can affect the oxidative burst in both phagocytic and nonphagocytic cells. For example, neutrophils from Se deficient rats exhibited reduced oxidative burst when incubated for prolonged periods with stimulants such as phorbal myristate acetate (PMA) or opsonized zymosan (12). This decreased oxidative burst was due to inadequate metabolism of H2O2, which was linked to lower activity of the NADPH-dependent superoxide-generating system. There are important feedback mechanisms involving levels of H2O2 and the strength of oxidative burst, and the neutrophil results support the notion that selenoproteins regulate this mechanism.
D. Se levels related to calcium and redox signaling in immune cells
1. H2O2 as a secondary messenger in leukocyte activation
H2O2 may enter the cell from extracellular sources by diffusion through the plasma membrane. Alternatively, H2O2 may be generated within immune cells on stimulation of a variety of receptor systems in a tightly regulated manner.
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This model helps explain two observations in H2O2-mediated signaling not addressed by the direct oxidation model just described: (1) there appears to be some degree of specificity in the oxidant actions of H2O2, and (2) removal of GPX does not increase the oxidant signaling of H2O2 as would be suspected, but actually decreases its actions (70). In this sense, the GPX and peroxiredoxin enzymes sense increases in H2O2, detoxify this molecule while simultaneously transmitting its oxidant signal to other signaling molecules that ultimately affects transcription. This mechanism does not replace the direct actions of H2O2 on Cys, but is thought to act in conjunction with the direct actions. Much of the data for this model have been obtained using yeast systems (53, 70, 254), but there is some evidence that it occurs in mammalian cells (91).
2. The relationship between Ca2+ flux and oxidative burst
Ca2+ plays a key role as a secondary messenger of signal transduction for a wide range of cell-types.
For immune cells, Ca2+ enters from extracellular spaces but is most often initiated from release of intracellular Ca2+ stores, predominantly located in the ER (143, 201).
Ca2+ flux is generated within seconds of receptor stimulation in immune cells and generally precedes any measurable oxidative burst, which typically occurs within minutes.
3. The effects of Se intake on Ca2+ flux and redox signaling in T cells
Human lymphocytes respond to Se supplementation with 100 μg Se/day as sodium selenite for 6 weeks predominantly by increasing mRNA encoding proteins involved in protein biosynthesis (192). Increased expression of the synthesis machinery may be required for increased production of selenoproteins themselves, or for protein factors that poise lymphocytes for stronger proliferative capacity.
Similar to other cell-types, a key redox mechanism by which high Se enhances the activation of T cells may involve the activation of the transcription factor, nuclear factor-kappa B (NFκB).
Binding of NFκB to target gene regions in Jurkat T cells is enhanced by reduction of a disulfide bond in the p50 subunit, which is regulated by reduced TXN (157). Levels of reduced Txn are increased with increased Txnrd1, and Txnrd1 activity is increased in T cells with increasing dietary Se (0.086–1.0 ppm) (102). This implies that higher Se and Txnrd1 activity would generate more effective NFκB binding.
4. Se related to calcium and redox signaling in phagocytes
Before one can appreciate the role of Se in redox signaling in phagocytes, the multiple roles that redox intermediates play in phagocyte function should be addressed.
Overall, there are several lines of evidence suggesting that sufficient levels of Se and selenoprotein are required for optimal oxidative burst, Ca2+ flux, and effector functions in phagocytes.
This enhanced baseline oxidative stress is not beneficial for cell signaling in the same manner as the receptor mediated oxidative burst. In this sense, Se deficiency increases baseline oxidative stress and thereby impairs phagocytic activation in the same manner. Not only is adequate Se required for optimal activation and function of these phagocytes, but also for expression of antioxidant selenoenzymes used to mitigate damage from mitochondrial and nonmitochondrial ROS. The Gpx enzymes can detoxify H2O2, whereas Txnrd1 is crucial for maintaining reduced thioredoxin and redox tone. Consistent with this notion, Txnrd1 mRNA and protein were shown to increase in macrophages on LPS-stimulation (35). Under resting conditions, macrophages lacking selenoproteins exhibited increased ROS production and without the ability to increase expression of Txnrd1, the macrophages cannot correct the redox tone from this increased ROS. Overall, it is evident that Se levels and specific selenoproteins are important for setting the redox tone in phagocytes before activation.
VII. Se and Immune Cell Effector Functions
A. T helper cell differentiation
1. Se and T helper differentiation
On TCR-stimulation of naive CD4+ T helper cell, these cells differentiate into effector T cells that play a central role in initiating and shaping immune responses. The number and type of CD4+ T helper cells that are generated during the first encounter with antigen-presenting cells substantially contribute to the outcome of the immune response. In particular, CD4+ T cells become polarized during activation into Th1, Th2, Th17, Treg, or other T helper subtypes (180, 213, 242).
Adequate Se intake appears to produce a more flexible differentiation state that is driven more by the environmental cues (e.g., cytokines) and antigen-presenting cell (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.
2. Regulatory T helper cells
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These data, although not conclusive, support the notion that increasing Se levels may promote a Treg phenotype from TCR-stimulated naïve CD4+ T cells and further investigation of how dietary Se influences immunoregulation via these important cells in vivo in needed.
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.
3. Epigenetic poising in naive T helper cells
Does Se intake affect epigenetic poising of naive CD4+ T helper cells?
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B. B cell function and antibody production
In a double-blind study more fully described next, 22 adult subjects received 50 or 100 μg/day Se Se supplementation as sodium selenite for 15 weeks, and this was shown to increase anti-poliovirus immunity in regards to several aspects of cell-mediated immunity (29).
C. Adherence and migration of leukocytes
1. Expression of adherence molecules
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VIII. Linkages Between Se and Human Disease
A. Se supplementation to boost anti-viral immunity
B. Critical illness stress-induced immune suppression
Thus, sepsis may trigger a pathogenic cycle in which sepsis and inflammatory cytokines decrease in SELP synthesis in the liver, which leads to lower Se levels in other tissues, which increases oxidative stress and further increases in inflammatory responses (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.
D. Intestinal inflammation and food-borne illnesses
E. Allergies and asthma
F. Cystic fibrosis
G. Autoimmunity
There are important links between Se levels and autoimmunity, with the best example being autoimmune thyroid diseases such as Hashimoto's thyroiditis (HT). Clinical studies have demonstrated that in patients with HT, Se supplementation reduced thyroid peroxidase autoantibody titers significantly as compared with the control subjects receiving placebo (250).
In addition, it remains unclear how Se supplementation may affect HT in patients with higher baseline Se status.
H. Se supplementation and aging immunity
The bioavailability of Se along with ∼30 other minerals and vitamins (V/M) has dramatic effects on the aging process (159). One notion of these nutrients in relation to aging is referred to as the triage theory, which proposes that when the dietary availability of a V/M is moderately inadequate, nature ensures that V/M-dependent functions that are essential from an evolutionary perspective are protected at the expense of those functions that are less essential. In other words, this guarantees that shortages do not have acute short-term negative consequences but may have long-term insidious effects that increase risk of diseases associated with aging (6). The triage theory does not imply that any particular V/M deficiency is the only cause of an age-related disease but rather that it is a contributing factor along with the sum of all contributing causal factors. The aging process leads to a progressive decline in many physiological processes, including immune responses (142). According to the triage theory, immune response would likely fall into the “less essential” category, with V/M deficiencies causing insidious problems that are less overt and accumulate over time. Consistent with this notion, there are immune deficiencies associated with V/M deficiencies that emerge mainly in postreproductive ages (158).
A small study involving 89 men and women aged 65 to 80 years evaluated several nutritional markers to determine which, if any, correlated with proliferative capacity of blood lymphocytes (264). Se was one of four nutrients found to positively correlate with proliferative capacity. Thus, the potential decline in Se status in the elderly may be a major contributing factor to decline immunity, although the data to support this are not entirely clear (224).
I. Lymphedema
Although results show a potential benefit of Se supplementation in attenuating lymphedema, meta-analysis have suggested that there are not enough data to reach a clear conclusion (54), and further research is needed.
J. Se supplementation and inflammation associated with diabetes
Some alarming and surprising data regarding Se supplementation and type-2 diabetes came to the forefront in 2009 when findings were published from the Se and vitamin E cancer prevention trial (SELECT) (145). SELECT was a phase-3 randomized, placebo-controlled trial of Se (200 μg/day from l-Se-Met), vitamin E (400 IU/day of all rac-α-tocopheryl acetate), or both for prostate prevention. SELECT was one of the largest human cancer prevention trials ever undertaken, but was discontinued well before the planned 12 year intervention period had been completed. Contributing to the early termination of this study was a slight but statistically nonsignificant increase in type-2 diabetes mellitus within the Se-supplemented group. It is important to note that the link between Se supplementation and type-2 diabetes in this study may have involved study design issues (93), and it was based on the observation that of a total of 1202 subjects, 58 diabetes cases occurred in the Se-alone group compared with 39 in the placebo group. Although these facts call into question the conclusions drawn from SELECT regarding diabetes risk from high Se intake, there are other findings that support such a correlation. For example, increased GPX1 activity has been hypothesized to interfere with insulin signaling.
The SELECT findings may be attributed to the fact that the serum Se levels of diabetics tend to be higher than those of diabetes-free controls not because they were taking supplemental Se, but due to disease-related changes of the serum protein levels. In a recent study, serum SELP concentrations were higher in patients with type-2 diabetes or prediabetes than those with normal glucose tolerance (275).
Although the direct effect of Se intake on glucose metabolism and insulin production by β-cells of the pancreas and activity of glycolytic and gluconeogenic liver enzymes have been demonstrated, understanding the effects on the immune system and its contributions in the pathogenesis of diabetes requires further investigation.
Referência :
Antioxid Redox Signal. 2012 Apr 1;16(7):705-43.
