Figure 1. Iron chelation therapy in SARS-CoV-2 infection.
The rapidity of the onset of inflammation in the acute phase of SARS-CoV-2 infection provokes increased ferritin production to permit adequate storage of iron and to deprive pathogen of iron. When the binding capacity of transferrin in the blood is exceeded, iron is found in the plasma as non-transferrin bound iron that changes to its redox active form termed labile plasma iron (LPI). LPI correlates with ferritin levels when in the cell contributes to the formation of reactive oxygen species (ROS) that results in tissue damage and subsequent fibrosis. Hyperinflammation with hyperferritinemia provokes cytokine release with macrophage activation, with iron initially accumulating in the reticuloendothelial macrophages and shedding of CD163 as marker of macrophage activation. The massive interleukin (IL)-1β release triggers a close autocrine loop leading to cytokine storm with dramatic IL-6, IL-18 and ferritin production.
Iron chelation therapy can interrupt these steps. a) deferoxamine (DFO) has a direct effect on ferritin since promotes ferritin degradation in lysosomes by inducing autophagy. Both deferiprone and deferasirox are likely to chelate cytosolic iron and iron which is extracted from ferritin prior to ferritin degradation by proteasomes. b) DFO can induce an up-regulation of IFN-γR2 expression on the cell surface on activated T cells thus restoring T cell response to SARS-CoV-2 infection. c) Deferasirox and DFO reduce fibrosis inhibiting the production of free radicals, macrophage tissue infiltration and cause a remarkable decrease of IL-6 levels.