Emerging Roles of the Iron Chelators in Inflammation

Abstract

Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

The Chelating Ability of Plant Polyphenols Can Affect Iron Homeostasis and Gut Microbiota

“…At a cellular level, iron regulatory proteins (IRP1 and 2) play an important role in the regulation of iron homeostasis by recognizing the iron-responsive elements (IREs) that are located in the untranslated regions of the mRNA encoding proteins that are involved in iron metabolism, such as DMT1, transferrin receptors, Ft, and FPN1, therefore modulating their translation [ 28 ]. At a systemic level, an important protein regulating iron homeostasis is represented by hepcidin, synthetized by the liver, which regulates the iron absorption, distribution, and storage in the different body districts [ 29 ].…”

“…At a systemic level, an important protein regulating iron homeostasis is represented by hepcidin, synthetized by the liver, which regulates the iron absorption, distribution, and storage in the different body districts [ 29 ]. In this way, increased levels of hepcidin reduce iron transport into the bloodstream, therefore affecting the iron distribution and storage, whereas reduced levels of hepcidin can cause an excess of iron in the bloodstream, Tf saturation, iron accumulation and overload, and hemochromatosis [ 28 , 30 ].…”

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

“…Iron metabolism is finely regulated in several physiological processes, and its alteration as in inflammation could actively participate to pathology onset [ 30 ]. Indeed, the use of iron chelators in clinical practice is prevalent, especially in hematological pathologies [ 31 ], and exhibits a promising proposal for other kind of diseases [ 17 , 32 , 33 , 34 , 35 ].…”

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

“…Imported Fe 3+ is transported to the endosome and reduced to Fe 2+ by the six-transmembrane epithelial antigen of prostate 3 (STEAP3), and is then transported into the cytoplasm via DMT1 ( Figure 2 ) [ 2 , 19 , 26 ]. FPN is the only protein responsible for the efflux of excess iron in cells and can be degraded by hepcidin [ 27 , 28 ]. Mice with cardiomyocyte-targeted deletion of FPN had myocardium dysfunction with iron accumulated in cardiomyocytes [ 29 ].…”