Targeted autophagy disruption reveals the central role of macrophage iron metabolism in systemic iron homeostasis

Author:

Taleb Meriem1,Maillet Isabelle2,Le Bert Marc2ORCID,Mura Catherine1

Affiliation:

1. Université d'Orléans, France

2. CNRS, Orléans, France

Abstract

Iron homeostasis depends on both intracellular control through iron-responsive proteins and the systemic level of iron through hepcidin-ferroportin axis. Indeed, the hormone hepcidin downregulates the ferroportin iron exporter to control iron recycling from macrophages and iron uptake from enterocytes. Here, we focused on the role of autophagy in macrophage iron metabolism and systemic iron homeostasis. Mice deficient for autophagy in macrophages (LysM-Atg5-/-) mimicked a primary iron overload phenotype, resulting in high ferroportin expression in both macrophages and enterocytes that correlated with marked parenchymal iron overload. Furthermore, LysM-Atg5-/- mice exhibited increased hematopoietic activity with no sign of anemia but correlating with rather high plasma iron level. Compared to wild-type cells, bone marrow-derived macrophages from LysM-Atg5-/- mice had significantly increased ferroportin expression and a decreased iron content, confirming high iron export. In erythrophagocytic macrophages autophagy regulates hemosiderin storage mechanisms as well as the degradation of ferroportin and subsequently its plasma membrane localization and iron export; further, ferroportin colocalization with hepcidin indicates hepcidin autocrine activity. Relatively high hepatic hepcidin expression, and decreased hepcidin level in the spleen of LysM-Atg5-/- mice correlating with low hemosiderin iron storage as well as in erythrophagocytic Atg5-/- macrophages were evidenced. Therefore, our results highligh the critical role of autophagy in macrophages for iron trafficking and systemic iron homeostasis. We propose that in macrophages, autophagy restricts ferroportin level and iron export resulting in hepcidin expression with an autocrine-paracrine effect that takes part in the regulation of the ferroportin expression in duodenal enterocytes.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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