The findings revise current understanding of how the body handles haemoglobin after red blood cell breakdown and may have implications for haemolytic and liver diseases.

Haemoglobin, the protein responsible for oxygen transport in red blood cells, is released when ageing red blood cells rupture in the spleen instead of being cleared by macrophages. In certain disorders, increased red blood cell destruction leads to elevated levels of free haemoglobin, which can be harmful. Until now, macrophages were considered the primary cells responsible for clearing free haemoglobin.

In a study published in EMBO Reports, researchers from IIMCB, in collaboration with the Mossakowski Medical Research Institute of the Polish Academy of Sciences and partners from Poland, Germany and Denmark, demonstrated that free haemoglobin is also effectively removed by liver sinusoidal endothelial cells (LSECs).

LSECs are known to function as an efficient blood “filter,” capturing potentially harmful circulating molecules. They also help regulate iron metabolism by initiating signals that limit iron release into the bloodstream in response to overload. The researchers showed that these roles converge in a newly identified function: LSECs actively take up free haemoglobin, initiate its safe degradation and contribute to maintaining iron balance.

Katarzyna Mleczko-Sanecka, head of the Laboratory of Iron Homeostasis at IIMCB and corresponding author of the study, said the project originated from observations made at the Mossakowski Institute. After macrophages were depleted in mice, significant amounts of free haemoglobin were still transported to the liver.

“They asked us to interpret this observation. The topic immediately struck us as particularly important and directed our attention to LSECs, which we had previously studied in the context of iron homeostasis. The observation made by our colleagues at the Mossakowski Institute initiated this project and several years of very fruitful collaboration between our teams,” she said.

The project also involved researchers from Aarhus University and University of Leipzig Medical Center. Collaboration with the Leipzig centre enabled the use of human liver cells to assess whether mechanisms observed in mice are also present in humans. Additional contributors included the Institute of Biochemistry and Biophysics PAS, the Maria Skłodowska-Curie National Research Institute of Oncology and the International Institute of Molecular Mechanisms and Machines PAS.

Researchers employed advanced methods, including flow cytometry, confocal microscopy imaging, proteomics and spectroscopic techniques to measure cellular iron levels.

A key breakthrough came from a global analysis of proteins in LSECs compared with vascular cells from other organs and macrophages.

“It turned out that in many respects LSECs resemble macrophages more closely than their endothelial counterparts in other tissues, which strongly pointed to their new role in iron recycling,” Mleczko-Sanecka said.

In one experiment, aged red blood cells were administered to mice and changes in liver vascular cells were analysed. Of thousands of proteins examined, only five showed altered abundance, including the two main haemoglobin subunits.

“This was the moment when we clearly saw that haemoglobin released in the spleen reaches the liver and is +eaten+ by LSECs,” she said.

The researchers stressed that the study does not provide an immediate therapy but describes a newly identified biological mechanism and outlines directions for further research.

The discovery that LSECs act as a haemoglobin filter raises questions about whether, in haemolytic diseases, excess free haemoglobin could overload these cells and impair their other functions.

It also prompts investigation into whether liver diseases might reduce the capacity of LSECs to clear haemoglobin and what systemic consequences this could have.

The study was financed by the Polish National Science Centre. (PAP)

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