Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance
Mild rupture of aged erythrocytes occurs in the spleen, resulting in hemoglobin (Hb) release, whereas pathological hemolysis characterizes several diseases. Hb detoxification is attributed to macrophages, but other routes of Hb clearance remain elusive. Here, we uncover that Hb uptake is chiefly executed by liver sinusoidal endothelial cells (LSECs) via macropinocytosis. Consistently, LSECs display proteomic signatures indicative of heme catabolism, ferritin iron storage, antioxidant defense, and macropinocytic capacity, alongside high iron content and expression of the iron exporter ferroportin. Erythrocyte/Hb transfusion assays demonstrate that splenic macrophages excel in erythrophagocytosis, while LSECs and Kupffer cells scavenge the spleen-borne hemolysis products Hb and erythrocyte membranes, respectively. High Hb doses result in transient hepatic iron retention, LSEC-specific induction of heme-catabolizing Hmox1, along with the iron-sensing Bmp6-hepcidin axis culminating in hypoferremia. Transcriptional induction of Bmp6 in LSECs is phenocopied by erythrocyte lysis upon phenylhydrazine and elicits a distinct transcriptional signature compared to iron. Collectively, we identify LSECs as key Hb scavengers, a function that establishes the spleen-to-liver axis for iron recycling and contributes to heme detoxification during hemolysis.
Authors
- Patryk Slusarczyk (ORCID: https://orcid.org/0000-0003-2383-3630)
- Aneta Jończy (ORCID: https://orcid.org/0000-0002-4333-6853)
- Marcin Skorzynski (ORCID: https://orcid.org/0000-0001-6665-9041)
- Morgane Moulin
- Marta Miączyńska (ORCID: https://orcid.org/0000-0003-0031-5267)
- Marta Chwałek (ORCID: https://orcid.org/0000-0002-0997-3381)
- Kevin J. Waldron (ORCID: https://orcid.org/0000-0002-5577-7357)
- Maria Kulecka (ORCID: https://orcid.org/0000-0002-9830-8892)
- Gabriela Zurawska (ORCID: https://orcid.org/0000-0003-1465-8957)
- Raghunandan Mahadeva (ORCID: https://orcid.org/0000-0001-5865-6430)
- Zuzanna Sas (ORCID: https://orcid.org/0000-0001-7815-7938)
- Kamil Jastrzębski (ORCID: https://orcid.org/0000-0001-6481-1759)
- Tomasz P. Rygiel (ORCID: https://orcid.org/0000-0003-4746-6505)
- Remigiusz Adam Serwa (ORCID: https://orcid.org/0000-0002-4684-3754)
- Izabela Rumieńczyk (ORCID: https://orcid.org/0000-0002-2957-8952)
- Mikula Michal
- Anders Etzerodt
- Georg Damm
- Rafał Mazgaj
- Daniel Seehofer
- Katarzyna Mleczko-Sanecka
Institutions
- Aarhus University (DK)
- Medical University of Warsaw (PL)
- International Institute of Molecular and Cell Biology (PL)
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL)
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- Mossakowski Medical Research Institute, Polish Academy of Sciences (PL)
- Leipzig University (DE)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-01-06
- DOI
- https://doi.org/10.1038/s44319-025-00673-5
- Citations
- 1
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 36.93
Funders
- Amgen
- European Commission
- Fundacja na rzecz Nauki Polskiej
- Międzynarodowy Instytut Biologii Molekularnej i Komórkowej w Warszawie
- HORIZON EUROPE Framework Programme
- European Regional Development Fund