Anemia of inflammation is a prevalent comorbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting ferroportin (FPN)–mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidin-induced degradation and/or by repression of FPN (Slc40a1) transcription via cytokine and Toll-like receptor (TLR) stimulation. Although the mechanisms underlying hepcidin-mediated control of FPN have been extensively studied, those inhibiting Slc40a1 messenger RNA (mRNA) expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signaling regulators of Slc40a1 mRNA repression downstream of TLRs and NF-κB signaling. Interestingly, the NF-κB regulatory hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand LPS, the cytokine TNFβ/LTA, and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the histone deacetylases (HDACs) HDAC1 and HDAC3 to the antioxidant response element (ARE) located in the Slc40a1 promoter. Accordingly, pretreatment with a pan-HDAC inhibitor abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NF-κB to repress Slc40a1 transcription. Consistently, recruitment of HDAC1 and HDAC3 to the Slc40a1 ARE after stimulation with heat-killed Staphylococcus aureus is dependent on NF-κB signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a1 triggered by signals from redox, metabolic, and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.

中文翻译：

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炎症驱动的 NF-κB 信号通过 HDAC1 和 HDAC3 抑制巨噬细胞中铁转运蛋白的转录


炎症性贫血是慢性炎症性疾病患者普遍存在的合并症。炎症通过限制铁转运蛋白 （FPN） 介导的铁从回收衰老红细胞的巨噬细胞输出而引起低铁血症和铁限制性红细胞生成。铁调素诱导的降解和/或通过细胞因子和 Toll 样受体 （TLR） 刺激抑制 FPN （Slc40a1） 转录，从而降低 FPN 的巨噬细胞表面表达。尽管铁调素介导的 FPN 控制机制已得到广泛研究，但抑制 Slc40a1 信使 RNA （mRNA） 表达的机制仍然未知。我们在用 TLR2/6 配体 FSL1 刺激的巨噬细胞中应用靶向 RNA 干扰和药理学筛选，并确定了 TLRs 下游 Slc40a1 mRNA 抑制和 NF-κB 信号传导的关键信号调节因子。有趣的是，NF-κB 调节枢纽与 TLR4 配体 LPS、细胞因子 TNFβ/LTA 和热灭活细菌驱动的 Slc40a1 mRNA 抑制同样相关。从机制上讲，用热灭活的金黄色葡萄球菌刺激巨噬细胞将组蛋白脱乙酰酶 （HDAC） HDAC1 和 HDAC3 募集到位于 Slc40a1 启动子中的抗氧化反应元件 （ARE）。因此，用 pan-HDAC 抑制剂预处理消除了响应炎症线索的 Slc40a1 mRNA 抑制，表明 HDAC 在 NF-κB 的下游起作用以抑制 Slc40a1 转录。一致地，在用热灭活的金黄色葡萄球菌刺激后，HDAC1 和 HDAC3 向 Slc40a1 ARE 的募集取决于 NF-κB 信号传导。这些结果支持一个模型，在该模型中，ARE 整合了由氧化还原、代谢和炎症途径信号触发的 Slc40a1 的转录反应。 这项工作确定了长期寻求的炎症时 Slc40a1 转录下调的机制，为在这个关键时刻进行治疗干预铺平了道路。