Macrophages support pathological erythropoiesis in polycythemia vera and β-thalassemia

Abstract

Regulation of erythropoiesis is achieved by the integration of distinct signals. Among them, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages to physiological and pathological conditions of enhanced erythropoiesis. We used mouse models of induced anemia, polycythemia vera and β-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively to recovery from induced anemia, as well as the pathological progression of polycythemia vera and β-thalassemia, by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a direct impact of macrophages on the proliferation and enucleation of erythroblasts from healthy individuals and patients with polycythemia vera or β-thalassemia. The contribution of macrophages to stress and pathological erythropoiesis, which we have termed stress erythropoiesis macrophage-supporting activity, may have therapeutic implications.

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Figure 1: WT mice depleted of macrophages have impaired recovery from induced anemia.
Figure 2: Clodronate treatment reverses pathological features of a mouse model of polycythemia vera.
Figure 3: Improvement of anemia and ineffective erythropoiesis in Hbbth3/+ mice 40 h after a single administration of clodronate.
Figure 4: Chronic clodronate administration improves anemia, ineffective erythropoiesis and RBC phenotypes in Hbbth3/+ mice.
Figure 5: Human macrophages promote proliferation and limit differentiation of primary human erythroblasts.
Figure 6: Model of macrophage function in normal and pathological erythropoiesis.

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Acknowledgements

We thank M. de Sousa and the members of the Pasta and Red Cells Society of New York for technical support and helpful discussions. In addition, we thank T. Ganz and E. Nemeth (University of California Los Angeles), R. Fleming (St. Louis University), C. Enns (Oregon Health and Science University) and N. Mohandas and Y. Ginzburg (New York Blood Center) for their very valuable expertise on iron metabolism and erythropoiesis and helpful discussions. This work was supported by the US National Institutes of Health (NIDDK-1R01DK090554 and NIDDK-1R01DK095112), FP7-HEALTH-2012-INNOVATION from the European Community, Rofar (The Roche Foundation for Anemia Research) and the Children's Cancer and Blood Foundation (S.R.), the American Portuguese biomedical research fund (APBRF, USA)/Inova grant (P.R.) and the Fundacao para a Ciencia e Tecnologia, Portugal (P.R., fellowship SFRH/BD/24813/2005). Hamp knockout mice were a gift from S. Vaulont (Institut National de la Santé et de la Recherche Médicale), S. Rivera and T. Ganz (University of California Los Angeles).

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P.R. collected and analyzed the data, designed the experiments and wrote the manuscript. C.C. conducted the experiments, analyzed data and revised the manuscript. S. Gardenghi, L.B., R.G. and B.J.C. conducted the experiments, analyzed data and reviewed the manuscript. E.G. and M.F.M. maintained the mouse colony and performed animal experiments. R.L.L. and O.A.-W. provided mice with polycythemia vera and samples from humans with polycythemia vera and reviewed the manuscript. B.L.E. developed and provided the mice with polycythemia vera and reviewed the manuscript. N.V.R. provided clodronate liposomes and reviewed the manuscript. S. Ghaffari contributed vital reagents and reviewed the manuscript. R.W.G. reviewed the manuscript. P.J.G. collected and provided human samples and reviewed the manuscript. S.R. designed the experiments, analyzed the data and wrote the manuscript.

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Correspondence to Stefano Rivella.

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Ramos, P., Casu, C., Gardenghi, S. et al. Macrophages support pathological erythropoiesis in polycythemia vera and β-thalassemia. Nat Med 19, 437–445 (2013). https://doi.org/10.1038/nm.3126

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