Cross-talk between iron metabolism and intestinal inflammation

描述（由申请人提供）：铁代谢紊乱，无论是遗传决定的还是继发于其他疾病的，都是相对常见的临床问题。我们对Hfe敲除（KO）小鼠（人类I型血色素沉着症（HH）模型）的初步研究表明，这些动物体内和体外的异常铁代谢与炎症反应减弱有关。患有I型HH的个体，以及Hfe KO小鼠，其肝细胞来源的铁调节肽hepcidin的循环水平异常低。结果，巨噬细胞内铁浓度降低，同时血清铁升高，后者导致金属在各组织中的病理性沉积。我们的研究结果表明，巨噬细胞内铁的减少会损害这些细胞产生TNF1和IL-6的能力，以响应革兰氏阴性细菌或LPS。这种异常在体内表现为沙门氏菌引起的小肠结肠炎严重程度的降低。在野生型（WT）小鼠和炎症性肠病（IBD）小鼠模型的进一步研究中，我们发现感染性和非感染性结肠炎都与hepcidin表达增加相关，阻断hepcidin表达可降低肠道炎症的严重程度。虽然hepcidin的增加是慢性炎症状态下贫血的一个众所周知的因素，但我们的实验表明，它也通过增加巨噬细胞内铁水平和促进促炎细胞因子的表达而参与炎症的发病机制。总的来说，我们的观察表明，铁代谢的变化对炎症反应有显著影响，相反，炎症与铁代谢的改变有关，铁代谢的改变增加了炎症介质的产生。阐明这种串扰的机制将促进基于操纵铁稳态的抗炎策略的发展。因此，我们提出(1)确定Hfe缺乏及其相关的hepcidin表达和巨噬细胞内铁的减少减轻肠道炎症的机制，(2)阐明导致hepcidin表达增加和伴随肠道炎症的铁代谢失调的机制，(3)评估抑制hepcidin表达的新策略对IBD小鼠模型肠道炎症严重程度的影响。

DESCRIPTION (provided by applicant): Disorders of iron metabolism, either genetically-determined or secondary to other illnesses, are relatively common cllinical problems. Our preliminary studies with Hfe knock-out (KO) mice, a model of human type I hemochromatosis (HH), have revealed that the abnormal iron metabolism in these animals is associated with attenuated inflammatory responses in vivo and in vitro. Individuals with type I HH, as well as Hfe KO mice, have abnormally low circulating levels of the hepatocyte-derived, iron-regulatory peptide hepcidin. As a result, there is a reduction of intra-macrophage iron concentrations accompanied by elevation of serum iron, with the latter leading to pathological deposition of the metal in various tissues. Our results indicate that the decrease of iron within macrophages impairs the ability of these cells to produce TNF1 and IL-6 in response to Gram- negative bacteria or LPS. The abnormality manifests in vivo as a reduction in the severity of Salmonella- induced enterocolitis. In additional studies with wild-type (WT) mice and with mouse models of inflammatory bowel disease (IBD), we found that both infectious and non-infectious forms of colitis are associated with increased expression of hepcidin, and that blocking hepcidin expression reduces the severity of intestinal inflammation. Although increased hepcidin is a well known factor in the anemia of chronic inflammatory states, our experiments suggest that it also contributes to the pathogenesis of inflammation by increasing intra- macrophage iron levels and promoting the expression of pro-inflammatory cytokines. Collectively, our observations indicate that changes in iron metabolism have a significant impact on the inflammatory response and, conversely, that inflammation is associated with alterations in iron metabolism that increase the production of inflammatory mediators. Elucidating the mechanisms responsible for this cross-talk will facilitate the development of anti-inflammatory strategies based on manipulating iron homeostasis. Therefore, we propose to (1) determine the mechanisms by which Hfe deficiency and the associated reduction in hepcidin expression and intra-macrophage iron attenuate intestinal inflammation, (2) elucidate the mechanisms that lead to the increased hepcidin expression and dysregulated iron metabolism that accompany intestinal inflammation, (3) evaluate the effect of a new strategy for inhibiting hepcidin expression on the severity of intestinal inflammation in mouse models of IBD.