On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Igor Theurl, Ingo Hilgendorf, Manfred Nairz, Piotr Tymoszuk, David Haschka, Malte Asshoff, Shun He, Louisa M.S. Gerhardt, Tobias A.W. Holderried, Markus Seifert, Sieghart Sopper, Ashley M. Fenn, Atsushi Anzai, Sara Rattik, Cameron McAlpine, Milan Theurl, Peter Wieghofer, Yoshiko Iwamoto, Georg F. Weber, Nina K. HarderBenjamin G. Chousterman, Tara L. Arvedson, Mary McKee, Fudi Wang, Oliver M.D. Lutz, Emanuele Rezoagli, Jodie L. Babitt, Lorenzo Berra, Marco Prinz, Matthias Nahrendorf, Guenter Weiss, Ralph Weissleder, Herbert Y. Lin, Filip K. Swirski

Research output: Contribution to journalArticlepeer-review

137 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)945-951
Number of pages7
JournalNature medicine
Volume22
Issue number8
DOIs
Publication statusPublished - 2016 Aug 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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