1 Department of Medicine, University of Verona-AOUI Verona , Verona, Italy .
2 CEINGE and Department of Biochemistry, Federico II University , Naples, Italy .
Antioxid Redox Signal. 2018 Jan 1;28(1):1-14. doi: 10.1089/ars.2017.7051. Epub 2017 Sep 6.
Iron overload (IO) is a life-threatening complication of chronic hemolytic disorders such as β-thalassemia. IO results in severe cellular oxidative damage, leading to organ failure. Peroxiredoxin-2 (Prx2), a typical 2-cysteine-(Cys)-peroxiredoxin, is an important component of the cytoprotective system, but its response to IO is still to be fully defined.
We studied the effects of IO on Prx2-knockout mice (Prx2). The absence of Prx2 enhanced toxicity due to IO on erythropoiesis. We found that IO failed to induce the typical hepcidin (Hamp) upregulation in Prx2 mice due to its failure to activate the signal transducer and activator of transcription-3 (STAT3) with intact Jak2 signaling. In Prx2 mice, the loss of Hamp response was also observed after administration of a single dose of oral iron. When lipopolysaccharide (LPS) was used to explore IL6-STAT3 activation in Prx2 mice, STAT3 activation and Hamp upregulation were once again defective. Treatment with PEP-fusion-recombinant-Prx2 (PEP Prx2) significantly increased STAT3 activation with upregulation of Hamp expression in both IO- and LPS-exposed Prx2 mice. We also confirmed the beneficial effects of PEP Prx2 on Hamp expression through STAT3 activation in β-thalassemic mice.
We propose that Prx2 plays a key role in responding to cytotoxicity of IO, directly targeting STAT3-transcriptional factor in a Jak2-independent fashion and regulating Hamp in response to canonical stimuli.
Collectively, our data highlight a novel role of Prx2 in iron homeostasis. Prx2 is a key cytoprotector against IO that is induced either by iron supplementation or due to chronic hemolysis as in β-thalassemia. Prx2 is required to support STAT3 transcriptional activity and regulation of Hamp expression. Antioxid. Redox Signal. 28, 1-14.
铁过载（IO）是β-地中海贫血等慢性溶血性疾病的一种危及生命的并发症。IO 导致严重的细胞氧化损伤，从而导致器官衰竭。过氧化物还原酶-2（Prx2）是一种典型的 2-半胱氨酸（Cys）-过氧化物还原酶，是细胞保护系统的重要组成部分，但它对 IO 的反应仍有待充分确定。
我们研究了 IO 对 Prx2 敲除小鼠（Prx2）的影响。由于 IO 导致红细胞生成毒性增强，Prx2 缺失。我们发现，由于 Jak2 信号完整，IO 未能激活信号转导子和转录激活子 3（STAT3），因此未能诱导典型的铁调素（Hamp）上调。在 Prx2 小鼠中，单次口服铁给药后也观察到 Hamp 反应丧失。当使用脂多糖（LPS）探索 Prx2 小鼠中的 IL6-STAT3 激活时，STAT3 激活和 Hamp 上调再次出现缺陷。PEP 融合重组 Prx2（PEP Prx2）治疗显著增加了 STAT3 激活，并上调了 IO 和 LPS 暴露的 Prx2 小鼠中的 Hamp 表达。我们还通过 STAT3 激活证实了 PEP Prx2 在β-地中海贫血小鼠中对 Hamp 表达的有益作用。
我们提出 Prx2 在应对 IO 的细胞毒性中起关键作用，直接靶向 Jak2 非依赖性 STAT3 转录因子，并调节 Hamp 对经典刺激的反应。
总之，我们的数据突出了 Prx2 在铁稳态中的新作用。Prx2 是一种针对 IO 的关键细胞保护剂，无论是通过铁补充还是由于β-地中海贫血等慢性溶血引起的。Prx2 是支持 STAT3 转录活性和 Hamp 表达调节所必需的。抗氧化剂。氧化还原信号。28，1-14。
