Is extracellular ferritin is an endogenous danger signal that exacerbates inflammation?

细胞外铁蛋白是加剧炎症的内源性危险信号吗？

• 批准号: MR/Y014065/1
• 负责人: Rebecca Coll
• 金额: $ 79.45万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY014065%2F1
• 关键词: extracellular; ferritin; endogenous; danger; signal

Excessive inflammation contributes to the development of many acute and chronic human diseases including acute respiratory distress syndrome (ARDS) and Alzheimer's Disease. It is therefore crucial to understand how inflammation is exacerbated during the immune response. Levels of a protein called ferritin in blood are commonly used by doctors as a measure of inflammation, but interestingly ferritin's normal role is to store iron inside cells and we do not fully understand what it does outside the cell. Recent research suggests that ferritin has direct effects on immune cells and our preliminary data show that ferritin is released from immune cells called macrophages during a process called pyroptosis. We have also found that extracellular ferritin can activate macrophages, triggering inflammation through a protein complex called the inflammasome. This suggest that extracellular ferritin may be a signal for danger that the immune system reacts to causing a feedback loop of excessive and damaging inflammation. Interestingly, we have recently observed that in ARDS some patients (approx. 30%) have very high ferritin levels (hyperferritineaemia). The patients with hyperferritineaemia are at a higher risk of dying than patients with lower ferritin levels and high ferritin is also associated with high levels of the inflammasome protein interleukin-18 (IL-18) and other indicators of tissue damage in the lung. This suggests that hyperferritineaemia and inflammasome activation might contribute to the development of severe ARDS. Our research proposal aims to investigate the molecular mechanisms underlying the inflammatory response to ferritin by identifying the receptor for ferritin on macrophages and how it triggers inflammatory signals. We will then examine inflammasome activation and the role of ferritin in samples from patients with ARDS compared to healthy people. We will see if we can block inflammation in these cells by interfering with the inflammasome or ferritin signalling pathway. Finally we will examine how ferritin and inflammasome signalling may cause damage to other cells in the lung called epithelial and endothelial cells which get damaged by inflammation in ARDS. Understanding the role of extracellular ferritin in inflammation could pave the way for the development of targeted anti-inflammatory therapies for ARDS and other inflammatory diseases.

过度的炎症导致许多急性和慢性人类疾病的发展，包括急性呼吸窘迫综合征（ARDS）和阿尔茨海默病。因此，了解炎症在免疫反应期间如何加剧至关重要。血液中一种名为铁蛋白的蛋白质的水平通常被医生用作炎症的衡量标准，但有趣的是，铁蛋白的正常作用是将铁储存在细胞内，我们并不完全了解它在细胞外的作用。最近的研究表明，铁蛋白对免疫细胞有直接的影响，我们的初步数据表明，铁蛋白是从免疫细胞释放称为巨噬细胞在一个过程中称为pyroptosis。我们还发现细胞外铁蛋白可以激活巨噬细胞，通过一种称为炎性小体的蛋白质复合物引发炎症。这表明，细胞外铁蛋白可能是免疫系统对引起过度和破坏性炎症的反馈回路作出反应的危险信号。有趣的是，我们最近观察到，在ARDS中，一些患者（约。30%）具有非常高的铁蛋白水平（高铁蛋白血症）。患有高铁蛋白血症的患者比具有较低铁蛋白水平的患者处于更高的死亡风险，并且高铁蛋白还与高水平的炎性体蛋白白细胞介素-18（IL-18）和肺中组织损伤的其他指标相关。这表明高铁蛋白血症和炎性小体激活可能有助于严重ARDS的发展。我们的研究计划旨在通过鉴定巨噬细胞上铁蛋白的受体以及它如何触发炎症信号来研究铁蛋白炎症反应的分子机制。然后，我们将研究炎症小体激活和铁蛋白在ARDS患者样本中的作用，并与健康人进行比较。我们将看看是否可以通过干扰炎性小体或铁蛋白信号通路来阻断这些细胞中的炎症。最后，我们将研究铁蛋白和炎性体信号传导如何对肺中的其他细胞（称为上皮细胞和内皮细胞）造成损伤，这些细胞在ARDS中被炎症损伤。了解细胞外铁蛋白在炎症中的作用可以为ARDS和其他炎症性疾病的靶向抗炎治疗的发展铺平道路。