Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The immune system relies on adequate dietary selenium intake and this nutrient exerts its biological effects mostly through its incorporation into selenoproteins. The selenoproteome contains 25 members in humans that exhibit a wide variety of functions. The development of high-throughput omic approaches and novel bioinformatics tools has led to new insights regarding the effects of selenium and selenoproteins in human immuno-biology. Equally important are the innovative experimental systems that have emerged to interrogate molecular mechanisms underlying those effects. This review presents a summary of the current understanding of the role of selenium and selenoproteins in regulating immune cell functions and how dysregulation of these processes may lead to inflammation or immune-related diseases.

Selenium (Se) is an essential micronutrient trace element and an established nutritional antioxidant. Low Se status exacerbates inflammatory bowel diseases progression, which involves hyper inflammation in the digestive tract. Se nanoparticles (SeNPs) exhibit anti-inflammatory activity accompanied by low toxicity, especially when decorated with natural biological compounds. Herein, we explored the beneficial effects of SeNPs decorated with Ulva lactuca polysaccharide (ULP) in mice subjected to the acute colitis model. We constructed SeNPs coated with ULP (ULP-SeNPs) in average diameter ~130 nm and demonstrated their stability and homogeneity. Supplementation with ULP-SeNPs (0.8 ppm Se) resulted in a significant protective effect on DSS-induced acute colitis in mice including mitigation of body weight loss, and colonic inflammatory damage. ULP-SeNPs ameliorated macrophage infiltration as evidenced by decreased CD68 levels in colon tissue sections. The anti-inflammatory effects of ULP-SeNPs were found to involve modulation of cytokines including IL-6 and TNF-α. Mechanistically, ULP-SeNPs inhibited the activation of macrophages by suppressing the nuclear translocation of NF-κB, which drives the transcription of these pro-inflammatory cytokines. ULP-SeNPs supplementation may offer therapeutic potential for reducing the symptoms of acute colitis through its anti-inflammatory actions.

Significance: The stimulation of certain surface receptors on immune cells triggers the release of calcium (Ca ²⁺ ) stored in the endoplasmic reticulum (ER). This Ca ²⁺ flux is required for efficient activation and function of immune cells, and involves the ER membrane Ca ²⁺ channel, the inositol 1,4,5-triphosphate receptor (IP3R). We found that stable expression of IP3R requires the addition of a fatty acid through a process called palmitoylation catalyzed by an enzyme complex composed of DHHC6 (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) and selenoprotein K (Selk) proteins. These findings provide new mechanistic insight into the selenium-sensitive fine-tuning of immune cell activation through posttranslational modification of the IP3R Ca ²⁺ channel. This study also reveals a novel DHHC6/Selk enzyme complex responsible for regulating stable expression of the IP3R.

Significance: Selenoprotein K (SelK) is an endoplasmic reticulum (ER) membrane protein, and its expression is sensitive to dietary selenium levels. A recently described role for SelK as a cofactor in catalyzing protein palmitoylation reactions provides an important link between low dietary selenium intake and suboptimal cellular functions that depend on this selenoprotein for palmitoylation. Recent Advances: A recent breakthrough provided insight into the contribution of SelK to calcium (Ca ²⁺ ) flux in immune cells. In particular, SelK is required for palmitoylation of the Ca ²⁺ channel protein, inositol-1,4,5-triphosphate receptor (IP3R) in the ER membrane. Without this post-translational modification, expression and function of the IP3R is impaired. SelK is required for palmitoylation of another transmembrane protein, CD36, and very likely other proteins. SelK serves as a cofactor during protein palmitoylation by binding to the protein acyltransferase, DHHC6, thereby facilitating addition of the palmitate via a thioester bond to the sulfhydryl group of cysteine residues of target proteins. Critical Issues: The association of DHHC6 and SelK is clearly important for immune cell functions and possibly other cell types. The step in the DHHC6 catalyzed S-acylation reaction on which SelK acts remains unclear and possible mechanisms of how the kinetics of the reaction are impacted by SelK binding to DHHC6 are presented here. Future Directions: Uncovering the specific role of SelK in promoting DHHC6 catalyzed protein palmitoylation may open a new line of inquiry into other selenoproteins playing similar roles as cofactors for different enzymatic processes. Antioxid. Redox Signal. 23, 854–862.

Summary: Dietary selenium (Se) is an essential micronutrient that exerts its biological effects through its incorporation into selenoproteins. This family of proteins contains several antioxidant enzymes such as the glutathione peroxidases, redox-regulating enzymes such as thioredoxin reductases, a methionine sulfoxide reductase, and others. In this review, we summarise the current understanding of the roles these seleno proteins play in protecting the cardiovascular system from different types of stress including ischaemia-reperfusion, homocysteine dysregulation, myocardial hypertrophy, doxirubicin toxicity, Keshan disease, and others.