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).