Iron homeostasis in chronic inflammation

Abstract

Inflammation induced anemia and resistance to erythropoietin are common features in patients with chronic kidney disease (CKD). Elevated levels of cytokines and enhanced oxidative stress, conditions associated with inflammatory states, are implicated in the development of anemia. Accumulating evidence suggests that activation of cytokine cascade and the associated acute-phase response, as it often occurs in patients with CKD, divert iron from erythropoiesis to storage sites within the reticuloendothelial system leading to functional iron deficiency and subsequently to anemia or resistance to erythropoietin. Other processes have also been shown to be involved in the pathogenesis of anemia provoked by the activated immune system including an inhibition of erythroid progenitor proliferation and differentiation, a suppression of erythropoietin production and a blunted response to erythropoietin. The present review concerns the underlying alterations in iron metabolism induced by chronic inflammation that result in anemia.

Role of iron homeostasis in trypanosomiasis-associated anemia

“…The difference observed between Tf-R1 and Tf-R2 during the chronic phase of infection could be attributed to the fact that only Tf-R1 is under regulation of cellular iron levels whereas Tf-R2 is not (Wallace et al, 2005). Furthermore, the moderate up-regulation of Tf-R1 could reflect that the cytosolic labile iron pool is high (data not shown), which in turn triggers directly/indirectly an increased ferritin expression (which is also observed here) (Balla et al, 2007). This would be in accordance with the expression pattern of the genes involved in iron metabolism since in the chronic phase only genes involved in processing and storage are increased, skewing the pathway towards intracellular storage (see Fig.…”

Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness

“…1,2 Diminished expression of hepcidin leads to excessive iron uptake and iron overload disease, hemochromatosis, while excessive expression of hepcidin probably contributes to the anemia of chronic disease. [3][4][5][6][7] Hepcidin expression is affected by hemojuvelin (HJV; HFE2), hemochromatosis protein (HFE), and transferrin receptor 2 (TFR2), since mutations causing their loss of function or localization result in inappropriately low levels of hepcidin and iron overload. [8][9][10] Patients with mutations of the genes encoding hepcidin or hemojuvelin exhibit the lowest levels of hepcidin and the most severe form of iron overload, juvenile hemochromatosis, associated with an early age of onset, severe iron deposits in the liver and heart, and hypogonadism.…”

Effect of angiotensin II on iron-transporting protein expression and subsequent intracellular labile iron concentration in human glomerular endothelial cells

“…52 In addition, FPN1 is regulated by intracellular iron at the transcriptional level. 53 The present data indicate that these proteins are upregulated in a sequential manner, that is, DMT1 protein was first to reach a peak at 6 h and then TfR protein reached a peak at 12 h, but FPN1 protein level remained constant while TfR and DMT1 proteins were being upregulated (Figure 2a). These phenomena may be interpreted in light of the fact that iron regulatory protein transiently facilitates replenishment of cytosolic iron in cells by increasing iron uptake through TfR and DMT1 while simultaneously decreasing iron sequestration in ferritin and suppressing iron export through FPN1 51 followed by stimulation of FRN1 expression by increased cytosolic iron.…”

“…These phenomena may be interpreted in light of the fact that iron regulatory protein transiently facilitates replenishment of cytosolic iron in cells by increasing iron uptake through TfR and DMT1 while simultaneously decreasing iron sequestration in ferritin and suppressing iron export through FPN1 51 followed by stimulation of FRN1 expression by increased cytosolic iron. 53 Next, we analyzed the state of iron in HGECs induced by Ang II by using a ferrous iron-specific fluorescence indicator, PG SK. Within cells, iron is stored in the protein ferritin or hemosiderin.…”