Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia.
Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia.
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DOI：
10.1182/bloodadvances.2022009307
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发表时间：
2023-07-25
期刊：
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
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赤铁酮会加剧中间型β-地中海贫血小鼠模型中的铁超载和无效红细胞生成。 β-地中海贫血的特点是慢性铁调素抑制和铁超负荷，即使在未接受输血的患者中也是如此。非输血依赖性β-地中海贫血 (NTDBT) 的 HbbTh3/+ (Th3/+) 小鼠模型部分重现了人类表型，但缺乏慢性铁调素抑制、成年期铁的渐进积累或在患者中观察到的铁负荷率的个体间差异。 Erythroferrone (ERFE) 是一种红细胞调节剂，可在红细胞生成增加期间抑制铁调素。 NTDBT 患者血清中的 ERFE 浓度与铁调素水平呈负相关，但变化范围很大，这可能解释了患者铁超负荷的变异性。为了分析高 ERFE 浓度对 NTDBT 中铁调素和铁超载的影响，我们将 Th3/+ 小鼠与红系 ERFE 过度表达转基因小鼠杂交。 Th3/ERFE 转基因小鼠围产期死亡率较高，但 E18.5 的胚胎表现出与 Th3/+ 小鼠相似的活力、外观和贫血影响。与 Th3/+ 同窝小鼠相比，成年 Th3/ERFE 小鼠具有类似的严重贫血，但表现出血清铁调素的更大抑制以及肝脏、肾脏和脾脏中铁积累的增加。 Th3/ERFE 小鼠的血清 ERFE 浓度比任一亲本品系高得多，这一发现可归因于较高数量的成红细胞和每个成红细胞产生的 ERFE 较高。 Th3/+ 和 Th3/ERFE 小鼠具有相似的红细胞计数和缩短的红细胞寿命，但 Th3/ERFE 小鼠在其较大的脾脏中具有增加的红细胞前体数量，表明无效髓外红细胞生成加重。因此，高 ERFE 浓度会增加地中海贫血小鼠非输血性铁超负荷和无效红细胞生成的严重程度，但不会显着影响贫血或溶血。
Erythroferrone exacerbates iron overload and ineffective erythropoiesis in a mouse model of β-thalassemia intermedia. β-thalassemia is characterized by chronic hepcidin suppression and iron overload, even in patients who have not undergone transfusion. The HbbTh3/+ (Th3/+) mouse model of nontransfusion–dependent β-thalassemia (NTDBT) partially recapitulates the human phenotype but lacks chronic hepcidin suppression, progressive iron accumulation into adulthood, or the interindividual variation of the rate of iron loading observed in patients. Erythroferrone (ERFE) is an erythroid regulator that suppresses hepcidin during increased erythropoiesis. ERFE concentrations in the sera of patients with NTDBT correlate negatively with hepcidin levels but vary over a broad range, possibly explaining the variability of iron overload in patients. To analyze the effect of high ERFE concentrations on hepcidin and iron overload in NTDBT, we crossed Th3/+ mice with erythroid ERFE–overexpressing transgenic mice. Th3/ERFE-transgenic mice suffered high perinatal mortality, but embryos at E18.5 showed similar viability, appearance, and anemia effects as Th3/+ mice. Compared with Th3/+ littermates, adult Th3/ERFE mice had similarly severe anemia but manifested greater suppression of serum hepcidin and increased iron accumulation in the liver, kidney, and spleen. The Th3/ERFE mice had much higher concentrations of serum ERFE than either parental strain, a finding attributable to both a higher number of erythroblasts and higher production of ERFE by each erythroblast.Th3/+ and Th3/ERFE mice had similar red blood cell count and shortened erythrocyte lifespan, but Th3/ERFE mice had an increased number of erythroid precursors in their larger spleens, indicative of aggravated ineffective extramedullary erythropoiesis. Thus, high ERFE concentrations increase the severity of nontransfusional iron overload and ineffective erythropoiesis in thalassemic mice but do not substantially affect anemia or hemolysis.
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影响因子：
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