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

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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.