Role of Iron Chelation in Inflammation and Infection

Abstract

Iron is an essential element for most forms of life, as its redox-cycling capabilities enable its participation in numerous physiological reactions. However, iron levels must be tightly regulated to avoid free iron toxicity via catalysis of reactive oxygen species (ROS), which activate pro-inflammatory pathways. Iron dysregulation and excessive ROS production (oxidative stress) have been linked to dysregulated immune response and persistent infections. Two well-known examples of pathology induced by these changes are sepsis and cystic fibrosis. At the present time, there are no specific approved treatments for immune dysregulation. Additionally, antibiotic-resistant infections are becoming more difficult to clear. Iron chelators are potentially capable of addressing both needs by restricting iron availability for ROS production and reducing bacterial growth through nutritional immunity. Thus, we sought to investigate the anti-inflammatory and anti-bacterial effects of iron chelation by using DIBI, a highly specific, synthetic iron chelator. DIBI’s efficacy in vivo was assessed in three murine models of sepsis (endotoxemia, CASP, and CASP-I) and it was compared to the FDA-approved iron chelators deferiprone, deferoxamine, and desferasirox. We found that DIBI effectively alleviated sepsis-induced leukocyte-endothelial interactions and preserved capillary perfusion in the intestinal microvasculature. Moreover, when administered in combination with an antibiotic, imipenem, DIBI reduced bacterial growth and improved survival outcome. In vitro, DIBI had a dose-specific effect on the secretion of IL-6 and IL-8 by nasal epithelial cells with cystic fibrosis disease-causing mutations. The lower studied dose of DIBI (25 μM) had a pro-inflammatory effect, whereas the higher dose (200 μM) had an anti-inflammatory effect. Overall, these findings suggest a promising role for the therapeutic application of DIBI, as a novel approach for attenuating the dysregulated inflammatory response and potential adjuvant in anti-bacterial therapy.