Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.

Malaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. Iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liver-derived hormone hepcidin. We examined the regulation of hepcidin during malarial infection in mice using the rodent parasite Plasmodium berghei K173 (PbK). Mice infected with PbK develop a severe anemia and die after 18 to 22 days without cerebral malaria. During the early phase of blood-stage infection (day 1 to 5), a strong inflammatory signature was associated with increased production of hepcidin. Between days 7 and 18, while infection progresses, red blood cell count, hemoglobin and hematocrit dramatically decreased. In the late phase of malarial infection, hepcidin production was reduced concomitantly to an increase in the mRNA expression of the hepcidin suppressor erythroferrone (ERFE) in the bone marrow and the spleen. Compared with wild-type mice, Erfe-/- mice failed to adequately suppress hepcidin expression after infection with PbK. Importantly, the sustained production of hepcidin allowed by ERFE ablation was associated with decreased parasitemia, providing further evidence that transient iron restriction could be beneficial in the treatment of malaria.