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

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 comprehensivearticle, 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. Antioxid. Redox Signal. 16, 705–743. I. Introduction II. Bioactive Forms of Se and Their Effects III. Incorporation of Dietary Se into Selenoproteins IV. The Selenoprotein Family A. An overview of selenoproteins B. Selenoprotein functions 1. Glutathione peroxidases 2. Thioredoxin reductases 3. Deiodinases 4. Selenoprotein P 5. Selenoproteins K and S 6. Other selenoprotein family members C. The hierarchy of selenoprotein expression V. Selenoprotein Expression in Immune Tissues and Cells A. Tissue and cellular distribution under physiological conditions B. Selenoprotein expression in immune cells and tissues in response to Se changes C. The selenoproteomic response during immune cell activation VI. Se and Redox Signaling in Immune Cells A. An overview B. Types of ROS important for immune cell signaling C. Se levels related to the production of ROS in immune cells D. Se levels related to calcium and redox signaling in immune cells 1. H2O2 as a secondary messenger in leukocyte activation 2. The relationship between Ca2+ flux and oxidative burst 3. The effects of Se intake on Ca2+ flux and redox signaling in T cells 4. Se related to calcium and redox signaling in phagocytes 5. A novel link between Selk and the calpain/calpastatin system VII. Se and Immune Cell Effector Functions A. T helper cell differentiation 1. Se and T helper differentiation 2. Regulatory T helper cells 3. Epigenetic poising in naive T helper cells B. B cell function and antibody production C. Adherence and migration of leukocytes 1. Expression of adherence molecules 2. Migration D. Se and eicosinoid synthesis in macrophages E. Phagocytosis F. Inflammation linked to ER stress VIII. Linkages Between Se and Human Disease A. Se supplementation to boost anti-viral immunity 1. Se levels can affect the virus itself 2. Human immunodeficiency virus 1/acquired immune deficiency syndrome 3. Influenza viruses 4. Poliovirus B. Critical illness stress-induced immune suppression C. Systemic inflammatory response syndrome D. Intestinal inflammation and food-borne illnesses E. Allergies and asthma 1. Epidemiology 2. Mouse models of allergic asthma 3. Intervention with Se supplementation for patients with asthma F. Cystic fibrosis G. Autoimmunity H. Se supplementation and aging immunity I. Lymphedema J. Se supplementation and inflammation associated with diabetes IX. Can Se Supplementation Be Targeted to the Immune System? X. Information Gaps and Future Directions