Review Zinc and its role in immunity and inflammation ☆ Paola Bonaventura a , Giulia Benedetti a , Francis Albarède b , Pierre Miossec a, ⁎ a Immunogenomics and Inflammation Unit and the Department of Clinical Immunology and Rheumatology, Hospices Civils de Lyon, EA 4130 University of Lyon 1, Hôpital Edouard Herriot, Lyon, France b CNRS UMR 5276 “Laboratoire de Géologie de Lyon”, Ecole Normale Supérieure, 46 Allée d'Italie, 69634 Lyon, France abstract article info Article history: Received 2 November 2014 Accepted 15 November 2014 Available online 24 November 2014 Keywords: Zinc Metallothioneins Inflammation Cytokines Immune diseases Rheumatoid arthritis Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in im- mune modulation has arisen. This review aims at describing the mechanisms involved in the regulation of Zn ho- meostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its avail- ability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and sys- tems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adap- tive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T help- er cell subsets are particularly susceptible to changes in Zn status. While acute Zn deficiency causes a decrease in innate and adaptive immunity, chronic deficiency increases inflammation. During chronic deficiency, the produc- tion of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory dis- eases, including rheumatoid arthritis. © 2014 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 2. Transport of zinc and its family members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 2.1. Entry (import) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 2.2. Exit (export) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 2.3. Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 3. Zinc functions inside cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 3.1. Structural, catalytic and co-catalytic roles of Zn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 3.2. Zinc as a neurotransmitter and secondary messenger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 3.3. Zinc regulation of proliferation and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 4. Role of zinc in the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 4.1. Zinc and the innate immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 4.2. Zinc and the adaptive immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 4.3. Zinc and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 5. Role of zinc in diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 6. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Autoimmunity Reviews 14 (2015) 277–285 ☆ PB is supported by the Marie Curie EUTRAIN project. This project has received funding from the 7th Framework program of the EU, SP3-People, support for training and career devel- opment for researchers (Marie Curie), Network for Initial Training (ITN), FP7-PEOPLE-2011-ITN, under the Marie Sklodowska-Curie grant agreement No 289903. GB is supported by the IHU prometteur OPERA; and Professor Miossec is a senior member of and supported by the Institut Universitaire de France. ⁎ Corresponding author at: Tel.: +33 4 72 11 74 87; fax: +3 34 72 11 74 29. E-mail address: miossec@univ-lyon1.fr (P. Miossec). http://dx.doi.org/10.1016/j.autrev.2014.11.008 1568-9972/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev