Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin downregulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189
IntroductionAnemia of chronic inflammation (ACI), also termed anemia of chronic disease, is the most frequent anemia in hospitalized patients and develops in subjects suffering from diseases with associated immune activation, such as infections, autoimmune disorders, cancer and end stage renal disease. 1,2 A major cornerstone in the pathophysiology of ACI is iron limited erythropoiesis, caused by iron retention within macrophages. 1,[3][4][5][6] Cytokines and most importantly the acute phase protein hepcidin promote macrophage iron retention by increasing erythrophagocytosis and cellular iron uptake and by blocking iron egress from these cells. 5,[7][8][9][10] The primarily liver derived peptide, hepcidin, exerts regulatory effects on iron homeostasis by binding to ferroportin, the only known iron export protein, thereby leading to ferroportin degradation and subsequently to inhibition of duodenal iron absorption and macrophage iron release. 5,6,11,12 The crucial role of hepcidin for the development of macrophage iron retention, hypoferremia and ACI is underscored by the observations that mice overexpressing hepcidin develop severe anemia, 7,13 that macrophage iron retention and hyperferritinemia are positively associated with hepcidin formation 5,14 and that injection of LPS into healthy volunteers results in hepcidin production and hypoferremia. 15 The expression of hepcidin in hepatocytes is regulated by multiple signals. 16 Iron overload induces the formation of bone morphogenetic proteins (BMPs) 17 and activates phosphorylation of Smad1/5/8 phosphorylation, 17-20 which forms a transcriptional activator complex with Smad4 to stimulate hepcidin transcription. [21][22][23] In mice, BMP6 appears to play a major role in hepcidin regulation, as BMP6 knock out mice have hepcidin deficiency resulting in systemic iron overload. 24,25 Hemojuvelin (HJV) or HFE2, a membrane bound GPI-anchored protein 26,27 acts as a BMP coreceptor and promotes hepcidin transcription. 21 In contrast, a soluble form of HJV (sHJV) blocks BMP6 and inhibits hepcidin expression. 28 The inflammation mediated activation of hepcidin is mainly transmitted via the IL6-inducible transcription factor Stat3. [29][30][31] In addition, Stat3 signaling is influe...