Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response

• Published in: PloS one Vol. 10; no. 8; p. e0136106
• Main Authors: Bonaccorsi-Riani, Eliano, Danger, Richard, Lozano, Juan José, Martinez-Picola, Marta, Kodela, Elisavet, Mas-Malavila, Roser, Bruguera, Miquel, Collins, Helen L., Hider, Robert C., Martinez-Llordella, Marc, Sanchez-Fueyo, Alberto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.08.2015; Public Library of Science (PLoS)
• Subjects: Allografts; Analysis; Animal models; Animals; Biology; Cell activation; Cell cycle; Cell Proliferation; Chelation; Clinical trials; Clonal deletion; Concanavalin A; Concanavalin A - toxicity; Councils; Cytokines; Cytokines - metabolism; Diet; Disease susceptibility; Gastrointestinal Microbiome; Gene expression; Hepatitis; Hepcidin; Hepcidins - metabolism; Homeostasis; Hospitals; Immune response; Immune system; Immunological tolerance; Immunology; Immunosuppression; Immunotherapy; Inflammation; Injection; Intestinal microflora; Iron; Iron - deficiency; Iron deficiency anemia; Kinases; Life sciences; Liver; Liver - drug effects; Liver - immunology; Liver - metabolism; Liver diseases; Liver Transplantation; Lymphocyte Activation; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes T; Male; Medical research; Medicine; Mice; Mice, Inbred C57BL; Microbiota; Microbiota (Symbiotic organisms); Mitogens; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Nutrient deficiency; Nutrition research; Oxidative stress; Rodents; Studies; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transplantation; Transplants & implants; United Kingdom > UK; Denmark; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0136106

Hepatic expression of iron homeostasis genes and serum iron parameters predict the success of immunosuppression withdrawal following clinical liver transplantation, a phenomenon known as spontaneous operational tolerance. In experimental animal models, spontaneous liver allograft tolerance is established through a process that requires intra-hepatic lymphocyte activation and deletion. Our aim was to determine if changes in systemic iron status regulate intra-hepatic lymphocyte responses. We used a murine model of lymphocyte-mediated acute liver inflammation induced by Concanavalin A (ConA) injection employing mice fed with an iron-deficient (IrDef) or an iron-balanced diet (IrRepl). While the mild iron deficiency induced by the IrDef diet did not significantly modify the steady state immune cell repertoire and systemic cytokine levels, it significantly dampened inflammatory liver damage after ConA challenge. These findings were associated with a marked decrease in T cell and NKT cell activation following ConA injection in IrDef mice. The decreased liver injury observed in IrDef mice was independent from changes in the gut microflora, and was replicated employing an iron specific chelator that did not modify intra-hepatic hepcidin secretion. Furthermore, low-dose iron chelation markedly impaired the activation of isolated T cells in vitro. All together, these results suggest that small changes in iron homeostasis can have a major effect in the regulation of intra-hepatic lymphocyte mediated responses.