Hepcidin regulation in the anemia of inflammation

Abstract

Purpose of review: Anemia is prevalent in patients with infections and other inflammatory conditions. Induction of the iron regulatory hormone hepcidin has been implicated in the pathogenesis of anemia of inflammation. This review outlines recent discoveries in understanding how hepcidin and its receptor ferroportin are regulated, how they contribute to anemia of inflammation, and how this knowledge may help guide new diagnostic and therapeutic strategies for this disease.

Recent findings: IL-6 is a primary driver for hepcidin induction in many models of anemia of inflammation, but the SMAD1/5/8 pathway also contributes, likely via Activin B and SMAD-STAT3 interactions at the hepcidin promoter. Hepcidin has an important functional role in many, but not all forms of anemia of inflammation, although hepcidin-independent mechanisms also contribute. In certain populations, hepcidin assays may help target therapy with iron or erythropoiesis-stimulating agents to patients who may benefit most. New therapies targeting the hepcidin-ferroportin axis have shown efficacy in preclinical and early clinical studies.

Summary: Recent studies confirm an important role for the hepcidin-ferroportin axis in the development of anemia of inflammation, but also highlight the diverse and complex pathogenesis of this disorder depending on the underlying disease. Hepcidin-based diagnostic and therapeutic strategies offer promise to improve anemia treatment, but more work is needed in this area.

Figure 1. Current model of hepcidin regulation by iron and inflammation

Iron stimulates hepcidin (HAMP) transcription through holo-transferrin (Fe-TF) and BMP6. Liver iron increases BMP6 expression in nonparenchymal cells through an unknown mechanism. Fe-TF is sensed by binding to transferrin receptor 1 (TFR1) and transferrin receptor 2 (TFR2). The hemochromatosis protein HFE is displaced from TFR1 by Fe-Tf binding. HFE and TFR2 functionally intersect with the BMP-SMAD1/5/8 pathway to modulate hepcidin transcription through mechanisms that are still being worked out, but may involve interactions with the BMP co-receptor hemojuvelin (HJV) and/or the BMP type I receptor ALK3. BMP6 binding to HJV, type II receptors (BMPRII) and type I receptors (BMPRI) induces phosphorylation of SMAD1/5/8 proteins, which complex with SMAD4 and translocate to the nucleus to bind 2 BMP responsive elements (BMP-RE) on the HAMP promoter, thereby inducing transcription. TMPRSS6 cleaves HJV to reduce BMP-SMAD1/5/8 signaling in response to iron deficiency. Neogenin (Neo) is an HJV interacting protein that may also be involved in hepcidin regulation. Inflammatory stimuli induce expression of IL6 and Activin B, which activate the JAK/STAT3 and BMPR/SMAD pathways respectively to induce hepcidin transcription. Hepcidin promotes the degradation of ferroportin (FPN) in enterocytes, macrophages, and hepatocytes to limit iron entry into the bloodstream.

Figure 2. Experimental agents targeting the hepcidin-ferroportin axis as therapeutic strategies for AI

Agents targeting the BMP/SMAD pathway include: LDN-193189 inhibiting BMP type I receptor activity; soluble hemojuvelin fusion protein (sHJV), heparin, and BMP6 antibody (Ab) sequestering BMP ligands; hemojuvelin (HJV) Ab neutralizing HJV function; and follistatin-315 sequestering Activin B. Agents inhibiting IL6-STAT3 signaling include: Siltuximab neutralizing IL6, hydrogen sulfide suppressing IL6 and STAT3, and Tocilizumab targeting the IL6 receptor (IL6R). Agents targeting hepcidin and ferroportin (FPN) include: hepcidin Ab, anticalins (PRS-080) and spiegelmers (NOX-H94) inhibiting hepcidin protein; hepcidin antisense oligonucleotides (ASO) targeting hepcidin mRNA; and FPN Ab (LY2928057) targeting the hepcidin binding site on FPN.