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 removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.

Monocyte differentiation and antigen-presenting functions

“…The elevated sodium level activates the macrophages to become antimicrobial in a nuclear factor of activated T cells 5 (NFAT5)-dependent manner 69 . In the kidney, resident macrophages have been shown to take up circulating immune complexes and trigger an Fcγ receptor IV (FcγRIV)-dependent inflammatory response 70 , whereas in the liver, LY6C + monocytes can ingest stressed and senescent erythrocytes, which induces them to differentiate into ironrecycling macrophages 71 . These studies provide a few new functional assessments for monocyte-derived macrophages.…”

Iron homeostasis: An anthropocentric perspective

“…phages can be temporarily recruited to the liver during increased erythrocyte clearance from circulation (23).…”

Differential miRNA Expression in the Liver of Balb/c Mice Protected by Vaccination during Crisis of Plasmodium chabaudi Blood-Stage Malaria

“…It is therefore rather likely that the liver, rather than the spleen, massively removes P. chabaudi -infected erythrocytes from circulation during crisis in vaccination-induced self-healing infections of P. chabaudi (Wunderlich et al, 2014). Very recently, the liver has been even described as the primary organ for a unique mechanism of rapid on-demand erythrocyte disposal (Theurl et al, 2016). …”