Role of hepcidin-ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation

Abstract

Anemia of chronic inflammation (ACI) is a frequently diagnosed anemia and portends an independently increased morbidity and poor outcome associated with multiple underlying diseases. The pathophysiology of ACI is multifactorial, resulting from the effects of inflammatory cytokines which both directly and indirectly suppress erythropoiesis. Recent advances in molecular understanding of iron metabolism provide strong evidence that immune mediators, such as IL-6, lead to hepcidin-induced hypoferremia, iron sequestration, and decreased iron availability for erythropoiesis. The role of hepcidin-ferroportin axis in the pathophysiology of ACI is stimulating the development of new diagnostics and targeted therapies. In this review, we present an overview of and rationale for inflammation-, iron-, and erythropoiesis-related strategies currently in development.

Keywords: Anemia; inflammation; iron metabolism.

Figure 1

Proposed steps in the cross-talk between erythropoiesis and iron metabolism in conditions associated with iron dysregulation. (A) In acute blood loss (I), resultant hypoxia leads to increased erythropoietin (II) and consequent increase in erythroferrone (II) which suppresses hepcidin (III) and enables an increase in iron absorption and iron recycling, resulting in increased circulating iron (IV) available for erythropoiesis. (B) In iron deficiency anemia, decreased circulation iron concentration (I) leads to anemia and resultant hypoxia which results in increased erythropoietin (II) and subsequently increased erythroferrone (III), suppressing hepcidin (IV) to increase iron absorption and recycling. (C) In anemia of chronic inflammation, IL-6 driven increase in hepcidin (I) results in the sequestration of iron in macrophages, enterocytes, and hepatocytes, decreasing iron release into the circulation (II). As a consequence, iron restricted erythropoiesis and anemia result in compensatory increase in erythropoietin (III) and erythroferrone (IV), the later providing negative feedback to suppress hepcidin (RBCs = red blood cells; Epo = erythropoietin; ERFE = erythroferrone).

Figure 2

Model of hepcidin’s effect on iron availability for erythropoiesis. Because hepcidin functions post-translationally to influence iron efflux from cells by binding and internalizing ferroportin 1, the only known iron exporter, present on cells involved in iron metabolism (e.g., macrophages), decreased hepcidin leads to more ferroportin 1 present on cell membranes and consequently more iron efflux into circulation where it is available for uptake by erythroblasts via iron loaded transferrin binding to transferrin receptor 1. This happens in iron deficiency anemia. Alternatively, when hepcidin is high, its binding of ferroportin 1 prevents iron egress from cells and results in iron sequestration within macrophages (e.g., splenic macrophages, involved in iron recycling from senescent red blood cells), leading to iron restricted erythropoiesis. This happens in anemia of chronic inflammation (TfR1 = transferrin receptor 1; FPN1 = ferroportin 1; Fe = iron; Fe-Tf = iron loaded transferrin).