title: On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver.
abstract: 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.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Heart Center Freiburg, University of Freiburg, Freiburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Piotr
authors.initials: P
authors.lastname: Tymoszuk
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Haschka
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Malte
authors.initials: M
authors.lastname: Asshoff
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Louisa M S
authors.initials: LM
authors.lastname: Gerhardt
authors.affiliation: Department of Internal Medicine III, Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Tobias A W
authors.initials: TA
authors.lastname: Holderried
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Sieghart
authors.identifier: 0000-0003-2265-1974
authors.initials: S
authors.lastname: Sopper
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Fenn
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Rattik
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: McAlpine
authors.affiliation: Department of Ophthalmology and Optometry, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Milan
authors.initials: M
authors.lastname: Theurl
authors.affiliation: Institute of Neuropathology, Freiburg University Medical Centre, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wieghofer
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weber
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nina K
authors.initials: NK
authors.lastname: Harder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Chousterman
authors.affiliation: Department of Oncology, Amgen Inc., Thousand Oaks, California, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Arvedson
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: McKee
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Fudi
authors.identifier: 0000-0001-8730-0003
authors.initials: F
authors.lastname: Wang
authors.affiliation: Austrian Drug Screening Institute, Innsbruck, Austria.
authors.forename: Oliver M D
authors.initials: OM
authors.lastname: Lutz
authors.affiliation: Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Rezoagli
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.affiliation: Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Berra
authors.affiliation: Institute of Neuropathology, Freiburg University Medical Centre, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Guenter
authors.identifier: 0000-0003-0709-2158
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
mesh_terms: D000740:Anemia; D000743:Anemia, Hemolytic; D000755:Anemia, Sickle Cell; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007249:Inflammation; D007501:Iron / Q000378:metabolism*; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D013154:Spleen; D000098742:Ferroportin
chemical_list: D000950:Antigens, Ly; D027682:Cation Transport Proteins; C494192:Ly-6C antigen, mouse; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C500399:TIM-4 protein, mouse; D000098742:Ferroportin; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007501:Iron