Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

Mild hemolysis of senescent erythrocytes occurs physiologically in the spleen, resulting in hemoglobin (Hb) release, whereas pathologic erythrocyte rupture characterizes several diseases. Iron recycling from Hb and Hb detoxification have been attributed to the sequestration of Hb-haptoglobin complexes by macrophages. However, we found the existence of additional efficient Hb clearance routes in mice. We identified liver sinusoidal endothelial cells (LSECs) as the primary cells responsible for Hb sequestration, a process that involves macropinocytosis and operates independently of the Hb-haptoglobin receptor CD163. LSECs expressed heme oxygenase 1 and hepcidin-controlled ferroportin and were the most efficient cellular scavengers of Hb at doses below and above the haptoglobin binding capacity. Erythrocyte transfusion assays further demonstrated that while splenic red pulp macrophages are adept at erytrophagocytosis, liver Kupffer cells and LSECs mainly clear erythrocyte ghosts and Hb, respectively, transported from the spleen via the portal circulation. High-dose Hb injections in mice resulted in transient hepatic iron retention and early activation of the gene encoding heme oxygenase 1 ( Hmox1 ) in LSECs. This response was associated with the transcriptional induction of the iron-sensing angiokine Bmp6 , culminating in hepcidin-mediated transient serum hypoferremia. Injection of Hb and iron citrate elicited distinct transcriptional signatures in LSECs, and the Bmp6 induction was phenocopied by erythrocyte lysis upon phenylhydrazine. Collectively, we propose that LSECs provide a key mechanism for Hb clearance, a function that establishes the spleen-liver axis for physiological iron recycling from Hb and contributes to heme detoxification during hemolysis, coupled with the induction of the BMP6-hepcidin axis, ultimately restoring iron homeostasis. Key points ### Competing Interest Statement The authors have declared no competing interest.