Iron is essential for numerous biological processes, including oxygen transport, DNA synthesis, and cellular respiration. However, tight regulation of iron balance is crucial, as both iron deficiency and iron overload can lead to severe health issues. At the Laboratory of Iron Homeostasis, we aim to elucidate iron regulatory mechanisms across tissues and cell types, with a particular focus on iron recycling from erythrocytes and the systemic sensing of body iron burden. Through this work, we advance the understanding of mammalian physiology and the pathogenesis of diseases associated with iron dyshomeostasis. 

Research Summary

One major aspect of our research focuses on iron recycling, a process primarily orchestrated by splenic red pulp macrophages, or RPMs, which break down aging erythrocytes and release iron back into the bloodstream. Despite representing the dominant source of bioavailable iron, knowledge about RPM biology and the mechanisms governing iron turnover efficiency remains limited. 

Our findings revealed a pronounced impairment of this process during aging. Specifically, we demonstrated that age-associated iron accumulation in RPMs leads to their functional decline and eventual demise, a challenge partially alleviated by dietary iron restriction in mice. 

Another major research line explores distinct functional and metabolic adaptations of RPMs in response to iron deficiency, shedding light on how the organism adjusts to restricted iron availability. 

In addition, our research identified liver sinusoidal endothelial cells, or LSECs, as the primary cell type responsible for the clearance of free hemoglobin from the circulation, thereby contributing to physiological iron recycling and hemoglobin detoxification, particularly under hemolytic conditions. 

Concurrently, we uncovered previously unrecognized mechanisms by which LSECs sense excessive systemic iron levels, including elevated hemoglobin burden. Our work also identified iron-triggered signaling via the transcription factor ETS1 and the p38/JNK MAPK pathway as a mechanism regulating Bmp6 expression, a key iron-sensing component of systemic iron control.

Scientific Impact

• We identified impaired iron recycling as an early hallmark of aging. 
• We deciphered how splenic macrophages adapt their phagocytic capacity and metabolism in response to nutritional iron deficiency. 
• We revealed an unexpected role of liver endothelium in the clearance of free hemoglobin under both physiological and hemolytic conditions. 
• We discovered a novel signaling pathway involved in iron sensing by liver endothelium.

Future Goals

• We will investigate how iron recycling efficiency shapes splenic immune functions and contributes to broader immune homeostasis. 
• We aim to establish defective iron recycling as a contributing factor in human disease. 
• We will further dissect the links between macrophage metabolism and iron recycling from erythrocytes. 

Collaborations 

We work closely with peers from the iron metabolism field, researchers in immunology, cancer biology, infectious diseases, and liver physiology, and experts in modern omic technologies to understand how different cell types cooperate to maintain iron balance and support immune function. These collaborations enable us to translate mechanistic insights from mouse models and cellular systems into human-relevant contexts, including primary liver cells. 

Comment

In our research, we are driven by the realization that long-standing assumptions about iron biology and macrophage function often capture only part of the underlying reality. By looking closely at how individual cell types, such as splenic macrophages and liver endothelial cells, adjust their clearance functions, signaling, and metabolism to changing iron availability, we see that iron homeostasis is not a fixed program but a highly plastic, cell-type-specific process. Each time we revisit pre-existing concepts through the lens of metabolic rewiring and tissue context, we uncover new layers of organization that reveal how elegantly systemic iron balance is maintained.  - Katarzyna Mleczko-Sanecka, PhD 

Primary murine LSECs performing uptake of fluorescently labeled hemoglobin. Illustration by Aneta Jończy.