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

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

Differential effects of Vav-promoter-driven overexpression of BCLX and BFL1 on lymphocyte survival and B cell lymphomagenesis

Overexpression of BCLX and BFL1/A1 has been reported in various human malignancies and is associated with poor prognosis and drug resistance, identifying these prosurvival BCL2 family members as putative drug targets. We have generated transgenic mice that express human BFL1 or human BCLX protein throughout the haematopoietic system under the control of the Vav gene promoter. Haematopoiesis is normal in both the Vav-BFL1 and Vav-BCLX transgenic (TG) mice and susceptibility to spontaneous haematopoietic malignancies is not increased. Lymphoid cells from Vav-BCLX TG mice exhibit increased resistance to apoptosis in vitro while most blood cell types form Vav-BFL1 TG mice were poorly protected. Both transgenes significantly accelerated lymphomagenesis in Eμ-MYC TG mice and, surprisingly, the Vav-BFL1 transgene was the more potent. Unexpectedly, expression of transgenic BFL1 RNA and protein is significantly elevated in B lymphoid cells of Vav-BFL1/Eμ-MYC double-transgenic compared to Vav-BFL1 mice, even during the preleukaemic phase, providing a rationale for the potent synergy. In contrast, Vav-BCLX expression was not notably different. These mouse models of BFL1 and BCLX overexpression in lymphomas should be useful tools for the testing the efficacy of novel human BFL1- and BCLX-specific inhibitors