Anemia of Inflammation: A Review

Abstract

Impaired iron homeostasis and the suppressive effects of proinflammatory cytokines on erythropoiesis, together with alterations of the erythrocyte membrane that impair its survival, cause anemia of inflammation. Recent epidemiologic studies have connected inflammatory anemia with critical illness, obesity, aging, kidney failure, cancer, chronic infection, and autoimmune disease. The proinflammatory cytokine, interleukin-6, the iron regulatory hormone, hepcidin, and the iron exporter, ferroportin, interact to cause iron sequestration in the setting of inflammation. Although severe anemia is associated with adverse outcomes in critical illness, experimental models suggest that iron sequestration is part of a natural defense against pathogens.

Keywords: Anemia; Cancer; Erythroferrone; Ferroportin; Hepcidin; Inflammation; Interleukin-6; Iron.

Figure 1

Inflammation stimulates increased production of the iron-regulatory peptide, hepcidin, by hepatocytes and the pro-inflammatory cytokine, IL-6, which suppresses erythropoiesis. Hepcidin binds the iron exporter, ferroportin (fpn), causing internalization and degradation of both proteins and decreasing delivery of iron from macrophages to developing erythrocytes. This impairs erythroid development and leads to anemia. Increased erythropoietic drive stimulates erythroid progenitors to release erythroferrone, a hormone that suppresses hepcidin expression. When inflammation resolves, hepcidin and IL-6 levels decline, allowing iron to be exported to from macrophages to erythrocytes and promoting erythropoiesis.

Figure 2

Inflammation and hepatocyte damage augment Hepcidin transcription and iron sequestration via several pathways. Lipopolysaccharide (LPS), released by bacterial infection, and the proinflammatory cytokine, HMGB1, activate toll-like receptor 4 (TLR-4) signaling, which increases IL-6 release by macrophages, while leptin and obesity also promote IL-6 release. IL-6 signaling leads to phosphorylation of Stat3 and increased Stat3 binding to the Hepcidin promoter, while endoplasmic reticulum (ER) stress in hepatocytes promotes CEBP-α binding to the Hepcidin promoter. Bone morphogenic protein (BMP) or activin signaling via ligands, including BMP2,4,6, and 9 and Activin B, activate receptors, such as BMP receptor-I, causing Smad phosphorylation and Smad binding to the Hepcidin promoter, which is required for Hepcidin transcription. The BMP co-receptor, hemojuvelin (HJV) interacts with the BMP receptor to enhance BMP signaling. Inflammation or obesity also promotes macrophage release of lipocalin, which can interact with bacterial siderophores to sequester iron.