3. Mechanisms of action of Ferritin
Ferritin serves to bind iron molecules and to store iron in a biologically available form for vital cellular processes while protecting proteins, lipids and DNA from the potential toxicity of this metal element. It has been shown that ferritin is composed of two isoforms H- and L-. Differently enriched ferritin is expressed in several tissues (62) and has different implications during inflammation (30). Ferritin and its subunits light chain ferritin (LHC) and heavy chain ferritin (HFC) showed in vivo and in vitro immunomodulatory effects (63). For example, HFC in vitrodirectly binds chemokine receptor 4 (CXCR4) and effect CXCR2- mediated ERK1/2activation (64). Despite the acute rise of blood value of ferritin is part of the normal systemic response to inflammation, a hyperferritinemic response is associated with a significantly increased mortality in septic children (65). Although the main modulator of ferritin levels is iron availability, its synthesis may also be regulated by different inflammatory cytokines such as IL-1β and IL-6 (66, 67). Indeed, serum ferritin is affected by up-regulation of hepcidin whose production, in turn, is stimulated by pro-inflammatory cytokines, particularly IL-6 (68). Ten Kate et al. found that in patients with AOSD the amount of iron bound to ferritin is significantly lower compared to samples from healthy controls, and in comparison to patients with hemochromatosis; however, the total amount of circulating iron is much higher than in controls. This suggests that in active AOSD the rapid synthesis of ferritin exceeds the rate of iron incorporation in ferritin (69). An aspect to be considered in viral infection is the impact of iron on regulation of T-lymphocyte sensitivity to the IFN-γ/STAT1 signalling pathway. Indeed, it is known that the refractoriness of T cells to the IFN-γ/STAT1 pathway has been attributed mainly to down-regulation of the IFN-γR chains, especially IFN-γR2. In human T lymphocytes, IFN-γR2 internalization occurs mostly in clathrin-coated pits independently from IFN-γ (70). Iron binds to cytoplasmic iron regulatory protein 1 (IRP1) and IRP2 which, in turn, regulates expression of proteins such as ferritin. In addition, there is a regulatory loop connecting nitric oxide (NO) and iron: on the one hand, NO modulates IRP activity (71, 72), and, on the other, iron impairs inducible NO synthase transcription. It was shown that iron is critical to determine IFN-γR2 internalization thus preventing the activation of the IFN-γ/STAT1 pathway in human T cells. Deferoxamine (DFO) can induce an up-regulation of IFN-γR2 expression on the cell surface only in activated T cells that have entered the cell cycle (73). This can restore T cell response to SARS-CoV-2 infection in two ways: a) restoring the sensitivity of T lymphocytes to IFN-γ, b) possibly inhibiting clathrin-mediated SARS-CoV-2 cell entry (74).