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.

过度炎症有助于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）和阿尔茨海默氏病。因此，了解在免疫反应过程中如何恶化炎症是至关重要的。医生通常将一种称为血液中的蛋白质水平用作炎症的量度，但有趣的是，铁蛋白的正常作用是将铁储存在细胞内，我们不完全了解其在细胞以外的影响。最近的研究表明，铁蛋白对免疫细胞有直接影响，我们的初步数据表明，在称为凋亡的过程中，铁蛋白是从称为巨噬细胞的免疫细胞中释放出来的。我们还发现，细胞外铁蛋白可以激活巨噬细胞，从而通过称为炎症体的蛋白质复合物触发炎症。这表明细胞外铁蛋白可能是危险的信号，即免疫系统会反应导致过度和破坏性炎症的反馈回路。有趣的是，我们最近观察到，在ARDS中，某些患者（约30％）的铁蛋白水平很高（高铁血症）。与铁蛋白水平较低的患者相比，高铁血症的患者死亡的风险更高，高铁蛋白的患者也与高水平的炎性蛋白蛋白白介素-18（IL-18）以及肺组织损伤的其他指标有关。这表明高铁血症和炎性体激活可能有助于严重的ARDS的发展。我们的研究建议旨在通过鉴定巨噬细胞上铁蛋白的受体及其如何触发炎症信号来研究对铁蛋白炎症反应的基础机制。然后，我们将检查与健康人相比，我们将检查炎性体激活和铁蛋白在ARDS患者中的作用。我们将通过干扰炎症体或铁蛋白信号通路来查看是否可以阻止这些细胞中的炎症。最后，我们将研究铁蛋白和炎性体信号传导如何对肺部的其他细胞损害，称为上皮细胞和内皮细胞，这些细胞因ARDS的炎症而受损。了解细胞外铁蛋白在炎症中的作用可能为开发针对ARD和其他炎症性疾病的靶向抗炎疗法铺平道路。