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

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）和阿尔茨海默病。因此，了解炎症如何在免疫反应中加剧是至关重要的。医生通常用血液中一种叫做铁蛋白的蛋白质的水平来衡量炎症，但有趣的是，铁蛋白的正常作用是在细胞内储存铁，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影响，我们的初步数据表明，铁蛋白在一个称为焦亡的过程中从称为巨噬细胞的免疫细胞释放出来。我们还发现细胞外铁蛋白可以激活巨噬细胞，通过一种叫做炎性体的蛋白质复合物引发炎症。这表明细胞外铁蛋白可能是一种危险信号，免疫系统反应引起过度和破坏性炎症的反馈循环。有趣的是，我们最近观察到，在急性呼吸窘迫综合征（ARDS）中，一些患者(大约。30%)有很高的铁蛋白水平（高铁血症）。高铁素血症患者的死亡风险高于铁蛋白水平较低的患者，高铁蛋白还与炎症小体蛋白白介素-18 （IL-18）和其他肺组织损伤指标的高水平相关。这表明高铁血症和炎性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识别巨噬细胞上的铁蛋白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，我们将检测急性呼吸窘迫综合征患者样本中的炎性体活化和铁蛋白的作用，并将其与健康人进行比较。我们将看看能否通过干扰炎性小体或铁蛋白信号通路来阻断这些细胞的炎症。最后，我们将研究铁蛋白和炎性小体信号如何导致肺中上皮细胞和内皮细胞的损伤，这些细胞在急性呼吸窘迫综合征中受到炎症的损害。了解细胞外铁蛋白在炎症中的作用可以为开发针对ARDS和其他炎症性疾病的靶向抗炎治疗铺平道路。

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.