Hypoferremic Response to Chronic Inflammation Is Controlled via the Hemojuvelin/Hepcidin/Ferroportin Axis and Does Not Involve Hepcidin‐Independent Regulation of FpnmRNA

IF 10.1 1区 医学 Q1 HEMATOLOGY
Siqi Liu, Sofiya Tsyplenkova, Carine Fillebeen, Kostas Pantopoulos
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Abstract

The iron regulatory hormone hepcidin contributes to the pathogenesis of anemia of inflammation (AI) by inhibiting the iron exporter ferroportin in target cells, causing hypoferremia. Under acute inflammation, hepcidin induction requires hemojuvelin (Hjv), a bone morphogenetic protein co‐receptor, while Fpn mRNA is also suppressed in a hepcidin‐independent manner. However, it is unclear whether, during chronic inflammation, Hjv and hepcidin‐independent Fpn mRNA regulation are critical for hypoferremia and AI. To address these questions, wild type and Hjv−/− mice, a model of hemochromatosis, were fed for 8 weeks an adenine‐rich diet to develop chronic kidney disease (CKD). Renal inflammation, accessed by increased Il6 mRNA expression, did not differ among genotypes. Hjv disruption did not mitigate the severity of kidney injury but suppressed the inflammatory induction of liver hepcidin. CKD triggered hypoferremia and mild anemia in wild type mice; however, Hjv−/− littermates maintained high serum iron and normal hemoglobin, consistent with a protective effect of Hjv/hepcidin deficiency. Notably, tissue Fpn mRNA levels were not affected by the inflammatory milieu of CKD. Following injection of wild type or Hjv−/− mice with heat‐killed Brucella abortus, Fpn mRNA was suppressed during the acute phase of inflammation but quickly recovered and persisted in the chronic phase. We conclude that Hjv deficiency reduces hepcidin levels and mitigates anemia in the CKD model, providing further support for pharmacological targeting of Hjv for the treatment of AI. Moreover, our data demonstrate that Fpn mRNA suppression only occurs under acute but not chronic inflammatory conditions and therefore cannot substantially contribute to AI pathogenesis.
低铁血症对慢性炎症的反应是通过haemjuvelin /Hepcidin/Ferroportin轴控制的,不涉及Hepcidin独立的FpnmRNA调节
铁调节激素hepcidin通过抑制靶细胞中的铁输出蛋白铁转运蛋白,导致低铁血症,参与炎症性贫血(AI)的发病机制。在急性炎症下,hepcidin诱导需要血幼蛋白(Hjv),一种骨形态发生蛋白协同受体,而Fpn mRNA也以hepcidin不依赖的方式被抑制。然而,目前尚不清楚在慢性炎症期间,Hjv和hepcidin独立的Fpn mRNA调控是否对低铁血症和AI至关重要。为了解决这些问题,野生型和Hjv - / -小鼠(血色素沉着症模型)被喂食富含腺嘌呤的饮食8周,以发展为慢性肾脏疾病(CKD)。肾炎症,通过增加Il6 mRNA表达,在基因型之间没有差异。Hjv破坏没有减轻肾损伤的严重程度,但抑制了肝磷脂的炎症诱导。CKD诱发野生型小鼠低铁血症和轻度贫血;然而,Hjv - / -窝鼠维持高血清铁和正常血红蛋白,与Hjv/hepcidin缺乏的保护作用一致。值得注意的是,组织Fpn mRNA水平不受CKD炎症环境的影响。在给野生型或Hjv - / -小鼠注射热杀死的流产布鲁氏菌后,Fpn mRNA在炎症急性期被抑制,但在慢性期迅速恢复并持续存在。我们得出结论,在CKD模型中,缺乏Hjv可降低hepcidin水平并减轻贫血,这进一步支持了Hjv治疗AI的药物靶向。此外,我们的数据表明,Fpn mRNA的抑制只发生在急性炎症条件下,而不是慢性炎症条件下,因此不能实质上促进AI的发病机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
15.70
自引率
3.90%
发文量
363
审稿时长
3-6 weeks
期刊介绍: The American Journal of Hematology offers extensive coverage of experimental and clinical aspects of blood diseases in humans and animal models. The journal publishes original contributions in both non-malignant and malignant hematological diseases, encompassing clinical and basic studies in areas such as hemostasis, thrombosis, immunology, blood banking, and stem cell biology. Clinical translational reports highlighting innovative therapeutic approaches for the diagnosis and treatment of hematological diseases are actively encouraged.The American Journal of Hematology features regular original laboratory and clinical research articles, brief research reports, critical reviews, images in hematology, as well as letters and correspondence.
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