血红素通过Toll样受体4和细胞外信号调节激酶信号通路激活巨噬细胞Hepcidin表达

Tangudu Nk, M. Vujic-Spasic
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引用次数: 10

摘要

身体健康需要对全身和细胞铁水平进行严格的调节。这种控制是由肝磷脂保证的,肝磷脂是一种主要由肝脏产生的小肽激素。缺乏hepcidin表达或突变影响hepcidin表达的调节因子,导致常见的遗传性铁疾病。Hepcidin也在髓细胞中表达,其表达在感染后和脂多糖反应中增加。我们的研究发现巨噬细胞在血红素过量的情况下迅速增加hepcidin的表达。此外,我们证明血红素在巨噬细胞中触发hepcidin激活的潜在机制取决于Toll样受体(TLR)-4和细胞外信号调节激酶(ERK)途径的作用。我们的数据表明,巨噬细胞局部产生的hepcidin对以游离血红素过量为特征的疾病病理的贡献,如某些细菌感染和溶血性疾病。最后,利用来自缺铁小鼠的巨噬细胞,我们证明缺铁对血红素诱导hepcidin并不重要,但对于维持巨噬细胞中hepcidin的基础表达是必需的。巨噬细胞中的hepcidin水平直接受这些细胞中Hfe的作用控制,这一发现扩大了我们对Hfe的认识,使其超越肝脏,仅作为铁水平的调节剂。
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Heme Activates Macrophage Hepcidin Expression via Toll like Receptor 4 and Extracellular Signal-Regulated Kinases Signaling Pathway
Tight regulation of systemic and cellular iron levels is required for good health. This control is ensured by hepcidin, a small peptide hormone produced predominantly by the liver. Lack of hepcidin expression or mutations affecting regulators of hepcidin expression, cause common genetic iron disorders. Hepcidin is also expressed in myeloid cells and its expression is increased after infections and in response to lipopolysaccharide. Our study uncovers that macrophages rapidly increase hepcidin expression in response to excess of heme. Moreover, we demonstrate that the underlying mechanism by which heme triggers hepcidin activation in macrophages depends on the Toll Like Receptor (TLR)-4 and the contribution of Extracellular Signal-Regulated Kinases (ERK) pathway. Our data propose the contribution of hepcidin, locally produced by macrophages, to the pathology of disorders characterized by excess of free heme, such as certain bacterial infections and hemolytic disorders. Finally, using macrophages from Hfe-deficient mice, we demonstrate that the lack of Hfe is not critical for the hepcidin induction by heme but is required to maintain basal hepcidin expression in macrophages. The findings that the levels of hepcidin in macrophages are directly controlled by the actions of Hfe in these cells expand our view on Hfe beyond the liver and as mere regulator of iron levels.
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