Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response.
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.
Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, Medical Research Council (MRC) Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London University, King's College Hospital, Denmark Hill, London, United Kingdom.
Eliano
E
Bonaccorsi-Riani
Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, Medical Research Council (MRC) Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London University, King's College Hospital, Denmark Hill, London, United Kingdom.
Richard
R
Danger
Liver Unit and Bioinformatic platform, CIBEREHD, Hospital Clinic Barcelona, Villaroel 170, Barcelona, Spain.
Juan José
JJ
Lozano
Liver Unit and Bioinformatic platform, CIBEREHD, Hospital Clinic Barcelona, Villaroel 170, Barcelona, Spain.
Marta
M
Martinez-Picola
Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, Medical Research Council (MRC) Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London University, King's College Hospital, Denmark Hill, London, United Kingdom.
Elisavet
E
Kodela
Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, Medical Research Council (MRC) Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London University, King's College Hospital, Denmark Hill, London, United Kingdom.
Roser
R
Mas-Malavila
Liver Unit and Bioinformatic platform, CIBEREHD, Hospital Clinic Barcelona, Villaroel 170, Barcelona, Spain.
Miquel
M
Bruguera
Department of Immunobiology, Division of Immunology, Infection & Inflammatory Disease, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, Stamford Street, London, United Kingdom.
Helen L
HL
Collins
Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, Stamford Street, London, United Kingdom.
Robert C
RC
Hider
Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, Medical Research Council (MRC) Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London University, King's College Hospital, Denmark Hill, London, United Kingdom.
Marc
M
Martinez-Llordella
Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, Medical Research Council (MRC) Centre for Transplantation, Faculty of Life Sciences & Medicine, King's College London University, King's College Hospital, Denmark Hill, London, United Kingdom.
Alberto
A
Sanchez-Fueyo
D000818:Animals; D049109:Cell Proliferation; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D064451:Hepcidins / Q000378:metabolism; D006706:Homeostasis; D000090463:Iron Deficiencies; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016031:Liver Transplantation; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D064451:Hepcidins; D003208:Concanavalin A