TY - JOUR
T1 - On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver
AU - Theurl, Igor
AU - Hilgendorf, Ingo
AU - Nairz, Manfred
AU - Tymoszuk, Piotr
AU - Haschka, David
AU - Asshoff, Malte
AU - He, Shun
AU - Gerhardt, Louisa M.S.
AU - Holderried, Tobias A.W.
AU - Seifert, Markus
AU - Sopper, Sieghart
AU - Fenn, Ashley M.
AU - Anzai, Atsushi
AU - Rattik, Sara
AU - McAlpine, Cameron
AU - Theurl, Milan
AU - Wieghofer, Peter
AU - Iwamoto, Yoshiko
AU - Weber, Georg F.
AU - Harder, Nina K.
AU - Chousterman, Benjamin G.
AU - Arvedson, Tara L.
AU - McKee, Mary
AU - Wang, Fudi
AU - Lutz, Oliver M.D.
AU - Rezoagli, Emanuele
AU - Babitt, Jodie L.
AU - Berra, Lorenzo
AU - Prinz, Marco
AU - Nahrendorf, Matthias
AU - Weiss, Guenter
AU - Weissleder, Ralph
AU - Lin, Herbert Y.
AU - Swirski, Filip K.
N1 - Funding Information:
This work was supported in part by US National Institutes of Health (NIH) grants 1R01HL095612, R01HL128264, R56AI104695 and the Massachusetts General Hospital's Howard M. Goodman Fellowship (to F.K.S.) and R01DK071837 (to H.Y.L.). I.T. was supported by the Max Kade Foundation and grants by the Austrian Science Fund (FWF) (P28302-B30 and P24749-B13)). I.H. (HI 1573/1-1, HI 1573/2-1) and G.F.W. were supported by the German Research Foundation. M. Nairz was supported by an FWF Erwin Schroedinger Fellowship (J3486-B13). L.M.S.G. and N.K.H. were supported by the Boehringer Ingelheim Fonds. F.W. was supported by the National Natural Science Foundation of China (31530034 and 31225013). We thank D. Capen for help in electron microscopy; N. Bonheur and M. Waring for help with cell sorting; A. Lindau for technical assistance; C. Haerdtner, J. Kornemann, and J. Zou for help with flow cytometry; D. Brown for interpretation of electron microscopy images; C. Robbins for the mouse drawing; and K. Joyes for editing the manuscript.
Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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-4neg 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-6Chigh 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.
AB - 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-4neg 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-6Chigh 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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UR - http://www.scopus.com/inward/citedby.url?scp=84978733946&partnerID=8YFLogxK
U2 - 10.1038/nm.4146
DO - 10.1038/nm.4146
M3 - Article
C2 - 27428900
AN - SCOPUS:84978733946
VL - 22
SP - 945
EP - 951
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 8
ER -