Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation.

中文翻译：

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HMGB1 介导的 EPO 信号传导限制会导致炎症性贫血。


炎症性贫血，也称为慢性病贫血，对促红细胞生成素 (EPO) 治疗无效，但 EPO 无效状态的机制尚不清楚。在这里，我们证明高迁移率族盒-1蛋白（HMGB1）是一种损伤相关分子模式分子，最近与脓毒症期间贫血的发展有关，在人类红细胞生成模型中导致EPO敏感的红系前体细胞的扩张减少和死亡增加。 HMGB1 显着减弱 EPO 介导的 Janus 激酶 2/STAT5 和 mTOR 信号通路的磷酸化。晚期糖化终末产物受体（唯一已知的由红系前体细胞表达的 HMGB1 受体）的基因消除并不能挽救 HMGB1 对人类或小鼠前体细胞中 EPO 信号传导的有害影响。此外，表面等离子共振研究强调了 HMGB1 干扰 EPO 和 EPOR 之间结合的能力。小鼠脓毒症发作后给予单克隆抗 HMGB1 抗体可部分恢复体内 EPO 信号传导。因此，HMGB1 介导的 EPO 信号传导限制导致炎症性贫血的慢性期。