On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver
Open accessAbstract
Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1(+)Tim-4(neg) macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)(high) Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6C(high) monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.
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As Kupffer cells gradually take over RBC recycling, they succumb to heme- and iron-mediated toxicity.
“As KC gradually take over the task of RBC recycling, they succumb to heme-and iron-mediated toxicity as well (Soares et al., 2014;Theurl et al., 2016).”
From Iron in infection and immunity (2020) · cites this paper as Theurl et al., 2016
In the paper’s main text (labeled Abstract in our copy; page unavailable), Kupffer cells express the iron exporter FPN1, and their numbers diminish after stressed-RBC challenge. But the paper identifies transient monocyte-derived macrophages as carrying most of the stressed RBCs and iron; it does not show Kupffer cells gradually taking over that recycling or dying from heme- and iron-mediated toxicity. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMacrophages and Kupffer cells scavenge heme from damaged or aged RBCs in the bone marrow, liver and spleen, extract the Fe2+ iron using HO-1, and then either export it back into the circulation through FPN or store it in ferritin intracellularly.
“Macrophages and Kupffer cells scavenge heme from damaged or aged RBCs in the bone marrow, liver and spleen, and extract the Fe2+ iron using HO-1 and then either exports it back into the circulation through FPN or stores it in ferritin intracellularly (Knutson et al., 2005; Theurl et al., 2016).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Theurl et al., 2016
Senescent RBCs are taken up by monocytes in the bloodstream and transported to both liver and spleen.
“Senescent RBCs are taken up by monocytes in the bloodstream and transported to both liver and spleen.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [24]
Accumulation of iron-recycling macrophages was exclusively observed in the liver, identifying the liver as the main organ for RBC recycling.
“Interestingly, accumulation of iron-recycling macrophages was exclusively observed in the liver, thus identifying the liver as the main organ for RBC recycling.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [24]
Chemokine-mediated monocyte recruitment is essential because if disrupted pharmacologically, damaged RBC accumulate in glomerular capillaries resulting in renal failure.
“This chemokine-mediated monocyte recruitment is essential because if disrupted pharmacologically, damaged RBC accumulate in glomerular capillaries resulting in renal failure [231].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [231]
Monocyte recruitment from the bone marrow to the liver is mediated by a liver-specific, Kupffer cell-derived CC-chemokine gradient of CCL2 and CCL3 that attracts CCR2+ CCR5+ monocytes.
“Indeed, monocyte recruitment from the BM to the liver is mediated by a liver-specific, KC-derived CC-chemokine gradient of CCL2 and CCL3 that attracts CCR2+ CCR5+ monocytes to the organ.”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [231]
Blood-derived monocytes fill the partial niche after Kupffer cell loss and differentiate into a transient macrophage population with high expression of CCR2.
“To compensate, blood-derived monocytes fill the partial niche after KC loss and differentiate into a transient macrophage population that has a unique phenotype including the high expression of the CC-chemokine receptor 2 (CCR2) [231].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [231]
In conditions of excessive RBC damage, liver macrophages (Kupffer cells) dominate RBC clearance.
“In conditions of excessive RBC damage, liver macrophages (Kupffer cells, henceforward abbreviated as KC) dominate RBC clearance (as detailed in “Liver—the iron regulatory organ” section) [231].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [231]
RPM and KC express the complete machinery for RBC clearance and heme iron recycling.
“It is well established that RPM and KC express the complete machinery for RBC clearance and heme iron recycling [72, 88, 231].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [231]
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- Authors
- Theurl, I., Hilgendorf, I., Nairz, M., Tymoszuk, P., Haschka, D., Asshoff, M., He, S., Gerhardt, L. M. S., Holderried, T. A. W., Seifert, M., Sopper, S., Fenn, A. M., Anzai, A., Rattik, S., McAlpine, C., Theurl, M., Wieghofer, P., Iwamoto, Y., Weber, G. F., Harder, N. K., Chousterman, B. G., Arvedson, T. L., McKee, M., Wang, F., Lutz, O. M. D., Rezoagli, E., Babitt, J. L., Berra, L., Prinz, M., Nahrendorf, M., Weiss, G., Weissleder, R., Lin, H. Y., & Swirski, F. K.
- Affiliations
- Harvard University (US)
- Innsbruck Medical University (AT)
- University Hospital Bonn (DE)
- University of Freiburg (DE)
- Amgen (United States) (US)
- Zhejiang University (CN)
- Austrian Drug Screening Institute (Austria) (AT)
- Corresponding author
- Lin, Herbert Y
- ORCID
- Theurl, Igor
- Hilgendorf, Ingo
- Nairz, Manfred
- Tymoszuk, Piotr
- Haschka, David
- Asshoff, Malte
- He, Shun
- Gerhardt, Louisa M S
- Holderried, Tobias A W
- Sopper, Sieghart
- Anzai, Atsushi
- Rattik, Sara
- McAlpine, Cameron
- Wieghofer, Peter
- Iwamoto, Yoshiko
- Weber, Georg F
- Chousterman, Benjamin G
- Arvedson, Tara L
- Wang, Fudi
- Lutz, Oliver M D
- Rezoagli, Emanuele
- Babitt, Jodie L
- Berra, Lorenzo
- Prinz, Marco
- Nahrendorf, Matthias
- Weiss, Guenter
- Weissleder, Ralph
- Lin, Herbert Y
- Venue
- Nature Medicine
- Published
- 2016-07-18
- Volume
- 22
- Issue
- 8
- Pages
- 945-951
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4957133
- OpenAlex
- W2493546904
- Cited by
- 412
- References
- 40
- Citations by year
- 2026: 26 · 2025: 29 · 2024: 40 · 2023: 45 · 2022: 52 · 2021: 47 · 2020: 57 · 2019: 39 · 2018: 35 · 2017: 38 · 2016: 4
- FWCI
- 23.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- BOA (University of Milano-Bicocca) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Funders
- National Institutes of Health (1r56ai104695-01)
- National Heart, Lung, and Blood Institute (R01HL128264, R01HL095612)
- National Institute of Allergy and Infectious Diseases (R56-AI104695)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071837, R01DK087727)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
- Keywords
- erythrocyte clearance, iron recycling, liver, Kupffer cells, monocyte recruitment, ferroportin 1, TIM-4, CSF-1, CSF2, Nrf2, hemolytic anemia, anemia of chronic disease, sickle cell disease, erythrocyte senescence, spleen
- MeSH terms
- Ferroportin, Anemia, Anemia, Hemolytic, Anemia, Sickle Cell, Animals, Antigens, Ly, Cell Differentiation, Disease Models, Animal, Erythrocytes, Inflammation, Iron, Kupffer Cells, Liver, Macrophages, Membrane Proteins, Monocytes, Spleen, Macrophage Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, Hepatocytes, Cation Transport Proteins, NF-E2-Related Factor 2, Mice
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