IRON OVERLOAD INDUCES GLUCOCORTICOID RESISTANCE IN MICE

Secondary iron overload (IO) is a pathological condition related to chronic disease (thalassemia, sickle cell disease) and multiple transfusions. It is associated with significant impairment in the endocrine system, including diabetes and dysregulation of the hypothalamus-pituitary-adrenal/gonad axis. Glucocorticoids are the end targets of the HPA axis and regulate the immune response and cellular metabolism through the activation of the glucocorticoid receptor (Gr). Here, we investigate the effect of secondary iron overload on glucocorticoid metabolism and its signaling through Gr.



Mice were subjected to chronic IO through Iron-dextran (1g/kg) injections once per week for 8 weeks, or to acute IO with 24h treatment. Subsequently, Gr activity was measured in the liver and spleen.



We show that both treatments were sufficient to induce systemic iron overload, with a profound iron deposition detected in the liver and spleen. This was correlated with a significant decrease in total Gr protein levels and its phosphorylated forms (pGrSer211/203). We further demonstrate that liver non-parenchymal cells and the splenic F4/80 positive cells are target cells with reduced Gr signaling activity. Interestingly, the endocrine status of the HPA axis was unaffected implicating the tissue-specific glucocorticoid resistance mediated by iron excess. Indeed, exogenous GC administration, both in vitro and in vivo, was not sufficient to activate Gr signaling in target cells. In contrast, reducing iron-mediated oxidative stress (by N-acetylcysteine or Ferrostatin-1) restored cellular responsiveness.



Our findings imply that iron retention in macrophages is a driver of glucocorticoid resistance in vivo, a condition that could be rescued by antioxidant drugs.