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

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.

Clinically inflammation can be evaluated by measuring serum ferritin levels, however, the primary function of ferritin is to store iron inside cells and its role in the inflammatory response is not fully understood. Macrophages are a major cellular store of ferritin and our preliminary data show that inflammasome activation and pyroptosis releases ferritin into the extracellular milieu. We have observed that extracellular heavy chain ferritin (FTH) can prime NLRP3 inflammasome activation and stimulate cytokine secretion from macrophages, suggesting that high levels of extracellular ferritin may act as a damage associated molecular pattern (DAMP), establishing an inflammatory feedback loop. Importantly, we have also observed that hyperferritineaemia defines a cohort of patients with ARDS who have a higher risk death. In these patients, high ferritin is associated with high levels of the inflammasome cytokine IL-18, and markers of epithelial and endothelial cell dysfunction, suggesting a mechanistic link between ferritin and inflammasomes in the pathogenesis of ARDS. The first aim of our research programme will be to identify the FTH receptor on human myeloid cells and to characterise the signalling pathway triggered by FTH using cell biology and RNA sequencing approaches. Our second aim will examine inflammasome activation in the alveolar compartment in ARDS and will determine whether ferritin mediates inflammasome activation in ARDS using existing patient samples from clinical trials. Our third aim will be to determine whether the ferritin-inflammasome axis causes endothelial and epithelial cell damage. By elucidating the role of extracellular ferritin in inflammation, this study aims to provide valuable insights for the development of effective anti-inflammatory interventions.