Article Type : Short commentary
Authors : Lissoni P, Valentini A, Rovelli F, Colciago M, Messina G, Lissoni A, Tassoni S and Fede GD
Keywords : Anaemia of chronic disease; Erythropoietin; Ferroportin, Hepcidin; Iron; Lactoferrin; Transferrin
Recent observations have
shown that there is a connection between iron metabolism andimmune functions,
including the anticancer immunity. Both iron deficiency and overload may induce
immunosuppression, even though for different reasons. Iron deficiency has been
shown to be associated with a reduced secretion of IL-2 that plays a fundamental
role in the regulation of the immune system, while iron overload may directly
induce toxic effects on the immune cells. The main link between iron metabolism
and the immunoinflammatory status is represented by hepcidin (HPC), a protein
produced by liver. HPC inhibits the activity of ferroportin, the protein
responsible for iron efflux into the blood, with a consequence iron
intracellular accumulation and increase in ferritin levels. Then, the enhanced
HPC production would be the main mechanism responsible for the anaemia of
chronic diseases. The importance of the connections between iron metabolism and
immune response is furtherly confirmed by the evidence that HPC production is
under a cytokine control, since it is stimulated by the inflammatory cytokines,
namely IL-6, and inhibited by IL-10, IL-2, erythropoietin, and hypoxia.
Recent experimental and clinical studies have shown
that iron is not essential for the only haemoglobin production, but also for
several other biological functions, mainly the immune responses [1]. Moreover,
the researches performed during the last years have allowed a better definition
of the different factors involved in iron metabolism. Iron entering the
circulation depends on two main sources, consisting of macrophages that recycle
iron from phagocytosed erythrocytes, and duodenal enterocytes that absorb iron
from the intestinal lumen through the cell surface protein, the natural
resistance-associated macrophage protein (NRAMP). Then, iron efflux into the
blood from both macrophages and duodenal cells is realized by the iron
transporter ferroportin (FPN), which is expressed on cell surface. Iron
circulates into the blood complexed to transferrin (TF). Finally, iron is taken
by the various cells through the transferrin receptor-type 1 (TFR1) that
internalized iron into the cell. TFR1 activity is stimulated by IL-10 and
inhibited by interferon-gamma. It has been also demonstrated the existence of a
type 2 of TFR, the TFR2, that is mainly expressed by hepatocytes and monocytes,
while TFR1 is mainly expressed by erythroid cells and monocytes. In any case,
both TF receptors may bind and internalize the iron bound on transferrin by the
endocytosis mechanism. In addition, in the last years, it has been demonstrated
that iron metabolism is under a complex regulation, namely exerted by the liber
peptide heptacidin (HPC). Other important factors involved in iron metabolism
are represented by the ferrireductase, which transforms the trivalent iron from
food in divalent iron to be transferred in the intestinal cells, the
ferroxidase, also termedhephaestin, which converts the divalent iron to
trivalent iron for the plasmatic transportation, since TF contain two-high affinity-binding
sites for the trivalent iron [2].
HPC is
a type II-acute-phase protein, mainly produced by liver, and it’s most
important function consists of the inhibition of FPN activity, with a
consequent reduced iron efflux from both macrophages and duodenal cells into
the blood, and a following iron intracellular sequestration, which allows an
increase in ferritin intracellular concentrations. Conditions which enhance the
demand for iron, including Iron deficiency and hypoxia, inhibit HPC production,
with a consequent increase in FPN levels and activity. The inhibitory action of
hypoxia on HPC secretion is mediated by the release of the hypoxia-induced
factor-1 (HIF-1). Then, a negative correlation has been observed between HPC
and FPN blood concentrations. In addition, HPC secretion has appeared to be
under a complex cytokine and neuroendocrine regulation. In more detail, HPC
secretion is stimulated by some inflammatory cytokines, in particular IL-6 [3],
and in a less manner by IL-1beta [4], while the role of TNF-alpha is till
controversial. The fundamental role of IL-6 in stimulating HCD secretion is
furtherly confirmed by the evidence that a long-term treatment with an
anti-IL-6 receptor antibody, such as tocilizumab, may inhibit HCD secretion and
improve the anaemic condition [5]. On the other side, HPC may exert a direct
inflammatory activity by stimulating the macrophage release of inflammatory
cytokines, including IL-6 and TNF-alpha. Then, HPC and IL-6 would be connected
by a positive feedback circuit. IL-22 has also appeared to promote HPC
secretion [6]. On the contrary, HPC secretion is inhibited by the
anti-inflammatory cytokine IL-10 [7]. HPC could be also inhibited by IL-2, since
IL-2 cancer immunotherapy has been proven to decrease ferritin levels and
enhance iron blood concentrations, with potential therapeutic efficacy in the
treatment of anaemia of chronic diseases [8], and on the other side iron
therapy has been seen to enhance IL-2 blood levels [9]. HPC secretion is also
stimulated by the adipokine leptin, and in obese individuals, adipocytes
themselves have appeared to produce HPC [10]. In contrast, vitamin D3 may
inhibit HPC production, with a potential therapeutic activity in some forms of
anaemia. In addition, because of the pro-inflammatory activity of HPC, the
inhibition of HPC played by vitamin D could constitute one of the mechanisms
responsible for its anti-inflammatory action, in addition to other mechanisms,
such as the inhibition of IL-8 secretion [11], and the stimulation of TGF-beta
production [12]. Testosterone has also appeared to inhibit HPC production.
Finally, erythropoietin (EPO) may also inhibit HPC secretion, by contributing
to enhance iron availability for haemoglobin synthesis and production [13].
Then, because of its fundamental role in iron metabolism, some understood
anaemic conditions may today be explained as depending on alterations of HPC
secretion, particularly in terms of abnormally enhanced HPC production.
HPC blood levels synthetise the status of iron
metabolism, and its relation to the immunoinflammatory status of subjects. High
levels of HPC have been found particularly in patients affected by anaemia of
chronic disease (ACD), also termed as the anaemia of inflammation [14]. ACD may
occur in pathologies characterized by an enhanced production of inflammatory
cytokines, including advanced neoplasms, chronic infections, and autoimmune
diseases, particularly in olde age, since aging is already characterized by an
enhanced production of IL-17, which is released from The 17 lymphocytes, and
stimulate the secretion of inflammatory cytokines by macrophages [15]. In
contrast, low levels of HPC have been found in patients with anaemia due to
iron deficiency, as well as in other conditions requiring an enhanced iron
availability for haemoglobin production, such as hypoxia, as in the case of
lung diseases. Moreover, the evidence of a decline in HPC levels has appeared
to be a predictive marker for the response to EPO therapy in anaemic cancer
patients. Abnormally high levels of HPC have been also seen in autoimmune
pathologies as consequence of the altered cytokine secretion, and this evidence
may explain the ACD, that may occur in autoimmunity. In fact, appositive
correlation has been found between IL-6 and HPC blood levels in patients with
chronic inflammatory diseases. On the same way,several histotypes of tumours,
particularly in the metastatic disease, have appeared to be characterized by
high HPC concentrations, but at present it is still unknown whether the
enhanced HPC secretion may depend on the presence of tumour itself or on other
concomitant conditions, such as the ACD, as well as HPC may exert a direct
pro-tumoral action. Iron is also essential for the neoplastic cells. Then, from
this point of view, HPC could promote cancer growth by inhibiting the activity
of FPN, with a consequent promotion of iron accumulation into cancer cells. In
fact, HPC expression is generally suppressed in cancer tissues. On the
contrary, the block of TFR1 on cell surface of cancer cells could counteract
the bound of iron-transferrin complex, and opposite tumour cell proliferation
[16].
Iron metabolism and immune system have appeared to be
connected by reciprocal influences, since iron concentrations have been proven
to influence the immune functions, and in turn the immune reactions may affect
iron metabolism. Iron deficiency has been found to be characterised by low
levels of IL-2, which become normal after iron supplementation [17]. In any
case, despite the complexity of the problem and the controversial results
reported in the literature, it is possible to affirm that both iron deficiency
and excess negatively influence the immune functions. Iron deficiency
immunosuppresses because of the need of iron for all cell functions, including
the immune cells. On the other side, iron overload also plays an
immunosuppressive action, because of iron toxicity, due to the generation of
reactive oxygen species (ROS), which allows an inflammatory status, and a
consequent inhibition of the anticancer immunity, since macrophage-related
chronic inflammation has appeared to suppress the immune reactions against cancer
growth [18]. An important role in the regulation of iron-immune system
interactions is played by HPC itself. In fact, HPC may directly influence the
immune functions, in particular the defence against microbial pathogens by
reducing the availability of iron,which is essential for the growth of
pathogens, as wellas for the normal human cells. As far as immune cells are
concerned, iron would be important particularly for T lymphocyte proliferation
and differentiation, whereas its influence on B lymphocytes and autoantibody
production is less evident [19]. In addition, it has been shown that the block
of TFR with strategiessuch as the administration of anti-TFR monoclonal
antibodies, has appeared to prolong the survival of allograft transplantation,
and completely abrogate cytotoxic T lymphocyte response, by suggesting a
fundamental role of TFR in mediating the immune reaction against organ
transplantation. In fact, TFR expression has been proven to be up-regulated
during T cell activation after its interaction with the antigen-major
histocompatibility complex, and the expression of IL-2 receptor [20]. Then, TF
and its receptor would be also involved in the maintenance of self-identity
mechanisms. Moreover, at present, it is known that that the immune system and
cytokine network are physiologically under a neuroendocrine central regulation,
namely played by the pineal gland through its main hormone melatonin (MLT)
[21], and brain opioid [22] and cannabinoid system [23]. However, no data are
available about the possible existence of a neuroendocrine influence on HPC
secretion. Then, at present it is still unknown whether the neuroendocrine
system may influence the immune functions, as well as iron metabolism, at least
in part through a modulation of HPC secretion.
Lactoferrin (LF) is an iron-binding glycoprotein of
the transferrin family, with particularly high concentrations in milk, but also
in other secretions. It is also released from neutrophils in the presence of
infections. LF plays a protective role in infections by locally sequestering
iron, that is essential for bacterial proliferation, then by acting as an iron
scavenger, but it does not supply the reticulocytes with iron. Moreover, recent
studies would suggest an involvement of LF in then regulation of cytokine and chemokine
secretions. In more detail, LF-induced iron sequestration has been proven to
reduce the production of inflammatory cytokines,including TNF-alpha, IL-6, and
IL-17, then by exerting an anti-inflammatory activity. Similar consideration
may be suggested in the case of the neoplastic diseases, because of iron
requirement by also tumour cells for theirgrowth.Moreover, LF has appeared to
be essential for the maturation and differentiation of both Tand Blymphocytes,
tostimulatedendritic cell functions as antigen presentingcells, ad stimulate
IL-12 production by macrophages. Finally, LF has been seen to inhibit IL-5
secretion from Th2 lymphocytes [24], with potential therapeutic impact in the
treatment of some forms of allergy, which is promoted by IL-5.
Until few years ago, iron was substantially taken into
consideration for its importance in haemoglobin production. On the contrary,
most recent researches have demonstrated that iron is involved in several other
biological functions, namely the immune functionless. Since iron availability
is mainly regulated by HPC, the main connection between iron metabolism and
immune functionless could be represented by HPC itself.