Magnesium and the Immune Response

Abstract Generation and maintenance of immunity is essential to the survival of an organism, but it comes at great metabolic and energetic costs. Therefore integrating cues indicative of nutritional status and environmental changes into signaling pathways regulating immune cell development, homeostasis, and activation is a necessity. The biologically essential ion magnesium (Mg 2+ ) plays an important role in these processes; however, our understanding of its cellular regulation and clinical relevance remained limited because molecular components of Mg 2+ homeostasis remain undefined. Mg 2+ permeable ion channels and transporters (such as Acdp2, MagT1, Mrs2, Paracellin-1, SLC41A1, SLC41A2, TRPM6, and TRPM7) have been identified at the molecular level only recently, and their characterization has provided new insights into the regulation of Mg 2+ homeostasis and how it affects immune responses. Gene deletion of Mg 2+ transporters leads to profound phenotypes with serious systemic effects. For example, TRPM7-deficient chicken DT40 B lymphocytes become growth deficient, leading to cell death within 48 h, TRPM7 deficiency in mice results in early embryonic lethality, and murine TRPM7 −/− thymocytes experience a developmental block at the double-negative stage (earliest thymocyte stage, negative for CD4 and CD8). TRPM7 and its closest homologue TRPM6 are unusual proteins because they represent the only known examples of a Ca 2+ and Mg 2+ permeable ion channels linked to a cytosolic kinase domain. The TRPM6/7 Ser/Thr kinases belong to a small family of atypical enzymes related to eukaryotic elongation factor-2 kinase, a kinase involved in modulating rates of protein translational elongation in response to nutritional mTOR signaling. The strong contribution of the mTOR pathway to immunity has emerged in multiple studies conducted predominantly in T lymphocytes. Recent discoveries revealed that mutations in Mg 2+ transport systems are the underlying cause of two hereditary diseases, human hypomagnesemia with secondary hypercalcemia (defects in TRPM6), and X-linked immunodeficiency with magnesium defect (XMEN). In particular, XMEN represents a novel type of immune disorder that can lead to severe and chronic Epstein–Barr virus infections and neoplasia, suggesting an unsuspected role for Mg 2+ as a second messenger in immunity. Future studies of Mg 2+ permeable ion channels and transporters expressed in immunocytes, which beyond MagT1 and TRPM6 include Mrs2, SLC41A1, SLC41A2, and TRPM7, will increase our knowledge about the potential role of Mg 2+ in the development and activation of the immune system.