Erythroferrone Represses Hepcidin Expression in a Mouse Model of Malaria

Introduction: Malaria, a mosquito-borne disease caused by a parasite, represents a major global health challenge in developing countries, resulting in over half a million deaths each year. Among the many clinical complications, the multiplication of the parasites in erythrocytes leads to a severe anemia secondary to hemolysis and increased erythrophagocytosis. Malarial anemia is also characterized by insufficient erythropoiesis to compensate for the loss of red blood cells, despite high erythropoietin (EPO) levels. Iron is an essential functional component of erythrocyte hemoglobin, therefore the production of erythrocytes requires the timely delivery of iron to erythroid precursors. The availability of iron for erythropoiesis is controlled by hepcidin-induced endocytosis and degradation of ferroportin, the iron exporter which delivers iron to plasma from absorptive enterocytes and erythrocyte-recycling macrophages. In the late phase of malarial infection, hepcidin is suppressed but the mechanism of suppression is unknown. The erythroid hormone erythroferrone (ERFE) has been recently described as an important regulator of hepcidin expression during increased erythropoietic activity. We assessed hepcidin and erythroferrone expression in mouse malaria and found that ERFE is necessary for hepcidin suppression during malaria infection.

Methods: To study the regulation of hepcidin in malaria, we used the rodent malaria parasite Plasmodium berghei K173 (PbK). Mice infected with PbK develop a lethal form of malaria with a high parasitemia and severe anemia and eventually die 18 to 20 days after infection. C57BL/6 mice were challenged intraperitoneally with 10⁶ PbK-parasitized erythrocytes. The parasitemia and the hematologic parameters, were monitored during 18 days (Table 1).

Results: Thirteen days after infection, mice showed a high parasitemia (20% of infected red blood cells) and significantly decreased RBC (3.8x10⁶/µL), hemoglobin concentration (6.6 g/dL) and hematocrit (21.5%) despite elevated serum EPO levels (not shown). We examined the time course of liver hepcidin expression and serum hepcidin concentration and found that hepcidin production was profoundly reduced 11 to 18 days after infection. As expected given the increase in EPO production after infection, hepcidin suppression was accompanied by an increase in erythroferrone mRNA expression in the bone marrow and the spleen. To determine whether ERFE plays a role in hepcidin suppression during malaria infection, we studied wild-type and Erfe-deficient mice after PbK infection. Erfe^-/- mice failed to adequately suppress hepcidin expression after infection with PbK compared with wild-type mice.

Figure 1

View largeDownload slide

Figure 1

View largeDownload slide

Close modal

Conclusion: Erythroferrone may be responsible for hepcidin suppression and compensatory iron acquisition during malaria infection.

Funded in part by ANR (project ANR-13-BSV3-0015-01) and FRM (project DEQ2000326528)