Cross-talk between iron metabolism and intestinal inflammation

铁代谢与肠道炎症之间的串扰

• 批准号: 8105669
• 负责人: Bobby Joseph Cherayil
• 金额: $ 43.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105669
• 关键词: Address; Affect; Anemia; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Attenuated; BMP6 gene; Blood Circulation; Bone Morphogenetic Proteins; Cells; Chronic; Colitis; Deposition; Development; Disease; Disease model; Dominant-Negative Mutation; Enterocolitis; Enterocytes; Equilibrium; Exposure to; Foundations; Genetic Transcription; Genetic Translation; Gram-Negative Bacteria; Hemochromatosis; Hepatocyte; Hereditary hemochromatosis; Homeostasis; Human; Immune response; Impairment; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-6; Investigation; Iron; Iron Metabolism Disorders; Iron Overload; Knock-out; Knockout Mice; Lead; Mediating; Messenger RNA; Metals; Modeling; Molecular; Mouse Strains; Mus; Pathogenesis; Pathway interactions; Peptides; Play; Process; Production; Role; Salmonella; Secondary to; Serum; Severities; Signal Transduction; T-Lymphocyte; TLR4 gene; Testing; Tissues; Translations; Up-Regulation; Wild Type Mouse; antimicrobial; base; cytokine; hepcidin; in vivo; iron metabolism; macrophage; metal transporting protein 1; mouse model; novel; novel strategies; research study; response; toll-like receptor 4

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. PUBLIC HEALTH RELEVANCE: This project is based on preliminary studies showing that altered iron homeostasis, specifically decreased expression of the iron-regulatory peptide hepcidin and a consequent reduction of intra-macrophage iron levels, impairs inflammatory responses in vitro and in vivo, and that intestinal inflammation is associated with an increase in hepcidin expression that contributes to the inflammatory process. We will extend these studies 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.

描述（由申请人提供）：铁代谢障碍，无论是遗传决定的或继发于其他疾病，是相对常见的临床问题。我们对Hfe基因敲除（KO）小鼠（人类I型血色素沉着症（HH）模型）的初步研究表明，这些动物的铁代谢异常与体内和体外炎症反应减弱有关。具有I型HH的个体以及Hfe KO小鼠具有异常低的肝细胞衍生的铁调节肽铁调素的循环水平。结果，巨噬细胞内铁浓度降低，同时血清铁升高，后者导致金属在各种组织中病理性沉积。我们的研究结果表明，巨噬细胞内铁的减少损害了这些细胞响应革兰氏阴性细菌或LPS产生TNF 1和IL-6的能力。这种异常在体内表现为沙门氏菌诱导的小肠结肠炎严重程度的降低。在对野生型（WT）小鼠和炎症性肠病（IBD）小鼠模型的其他研究中，我们发现感染性和非感染性结肠炎都与铁调素表达增加有关，并且阻断铁调素表达可降低肠道炎症的严重程度。尽管铁调素增加是慢性炎症状态贫血中的众所周知的因素，但我们的实验表明，它还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促成炎症的发病机制。总的来说，我们的观察结果表明，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，铁代谢的改变会增加炎症介质的产生。阐明负责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，我们建议（1）确定Hfe缺乏和相关的铁调素表达和巨噬细胞内铁减少减轻肠道炎症的机制，（2）阐明导致伴随肠道炎症的铁调素表达增加和铁代谢失调的机制，（3）评价抑制hepcidin表达的新策略对IBD小鼠模型中肠道炎症严重程度的影响。 公共卫生相关性：该项目是基于初步研究表明，改变铁稳态，特别是铁调节肽hepcidin的表达减少，从而降低巨噬细胞内铁水平，损害体外和体内的炎症反应，肠道炎症与hepcidin表达增加，有助于炎症过程。我们将扩展这些研究以（1）确定Hfe缺乏以及相关的铁调素表达和巨噬细胞内铁减少减轻肠道炎症的机制，（2）阐明导致铁调素表达增加和铁代谢失调的机制伴随肠道炎症，（3）评价抑制hepcidin表达的新策略对IBD小鼠模型中肠道炎症严重程度的影响。