Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response.
Iron Deficiency Impairs Intra-Hepatic Lymphocyte Mediated Immune Response.
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DOI：
10.1371/journal.pone.0136106
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sanchez-Fueyo A
中科院分区：
文献类型：
--
作者：
Bonaccorsi-Riani E;Danger R;Lozano JJ;Martinez-Picola M;Kodela E;Mas-Malavila R;Bruguera M;Collins HL;Hider RC;Martinez-Llordella M;Sanchez-Fueyo A
肝脏铁稳态基因的表达和血清铁参数预测临床肝移植后免疫抑制剂撤药的成功，这一现象被称为自发性操作耐受。在实验动物模型中，通过需要肝内淋巴细胞活化和缺失的过程建立自发的肝同种异体移植耐受。我们的目的是确定是否全身铁状态的变化调节肝内淋巴细胞反应。我们使用了淋巴细胞介导的急性肝脏炎症的小鼠模型，由刀豆球蛋白A（ConA）注射诱导，采用铁缺乏（IrDef）或铁平衡饮食（IrRepl）喂养的小鼠。虽然IrDef饮食诱导的轻度缺铁并没有显著改变稳态免疫细胞库和全身细胞因子水平，但它显著抑制了ConA激发后的炎性肝损伤。这些发现与在IrDef小鼠中注射ConA后T细胞和NKT细胞活化的显著降低相关。在IrDef小鼠中观察到的肝损伤减少与肠道微生物菌群的变化无关，并且采用不改变肝内铁调素分泌的铁特异性螯合剂进行复制。此外，低剂量的铁螯合显着损害了体外分离的T细胞的活化。总之，这些结果表明，铁稳态的微小变化可以在调节肝内淋巴细胞介导的反应中产生重大影响。
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.