Abstract：
Inflammatory bowel diseases (IBDs) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation is known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution, and that this in turn perpetuates the inflammation. This study analyzed human biopsies, animal models, and cellular systems to decipher the role of iron homeostasis in IBD. We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP) 1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular coculture model was established, which replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.
摘要：
炎症性肠病（IBD）是复杂的疾病。铁积聚在IBD患者发炎的组织中，然而，对于炎症的积累机制及其对炎症过程的影响尚不清楚。我们假设炎症改变了铁稳态，影响组织铁的分布，这反过来又延续了炎症。这项研究分析了人体活检，动物模型和细胞系统破译铁稳态在IBD中的作用。我们发现炎症介导的铁分布改变，和铁调节蛋白（IRP）1的铁解偶联激活。为了了解IRP1在这种炎症相关铁模式过程中的作用，建立了一种新的细胞共培养模型，复制了体内观察到的铁模式，并支持一氧化氮参与IRP1的激活和炎症中典型的铁模式。重要的是,从IBD小鼠模型中删除IRP1，铁的分布与肠道炎症。这些发现表明，IRP1在肠粘膜炎症反应的协调中起着核心作用，并且它是IBD治疗干预的可行候选者。
