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The ability to detect and destroy the pathogenic microorganisms that invade the body is the most essential to human survival. They are two main branches of the immune system that can ensure the efficient detection and removal of harmful microbes; the innate and adaptive immune systems. The innate immune system is a main defence mechanism that exists in mammals and other species including those in the plant kingdom. This system has two very important functions that are essential for defending the host against invading pathogens. First, it offers a physical barrier to invading microorganisms and secondly it primes the adaptive system with instructions on how to handle the invading microorganism (Chen et al., 2009).
The innate immune system is composed of various elements when acting against invading pathogens. It employs a myriad of cells to defend the body. These include natural killer cells, macrophages, dendritic cell (DC) and its precursors, neutrophils, basophils, tissue mast cells and epithelial cells. This system has evolved in order to differentiate between normal components that occur in the body self and pathogens. To achieve this, pattern recognition receptors (PRRs) recognize microbial components that are present in pathogen. These components are vital molecular structures that occur in almost all pathogens and are called pathogens associated molecular patterns (PAMPs). The PRRs are gremline-encoded and expressed as non-clonal receptors on all cells of given type (Akira et al., 2006). When binding to pathogen component, PRRs trigger an immediate response. Some PRRs act as phagocytic receptors, while others act as chemotactic receptors or induce the production of effecter molecules (Janeway et al., 2008). The immune system focuses in these molecules as they are essential for the pathogen to maintain and exert its virulence when attacking the (Medzhitov & Janeway, 2000).
Microbes that enter the tissue sites through the penetration of epithelial barrier are recognized by guard cells of the immune system: mast cells, macrophages and DCs. These cells have the ability to differentiate between the normal tissue components and the one that are indicative of infection. The differentiation is made by innate immune receptors including members of Toll-like receptors (TLRs) and Nucleotide-binding oligomerization domains (NODs) families (Cook et al., 2004).
TLRs detect different PAMPs and play a critical role in innate immunity. They share in protecting the body as they are the first line of defense against invading pathogens and play a significant role in inflammation, immune cell regulation, proliferation and survival. There are 11 members of the TLR family have been identified up to date. Some of them are located on the cell surface and they are TLR1, TLR2, TLR4, TLR5, and TLR6. The TLR3, TLR7, TLR8, and TLR9 are localized to the endosomal/lysosomal compartment (Takeda & Akira, 2005).
1.2 Toll-like receptor 3
TLR3 has been proposed to play a central role in the early recognition of viruses by sensing double stranded RNA (dsRNA). The exact role of TLR3 in viral infection is still controversial. TLR3 initiate specific signalling pathways, that leads to activation of the transcription factors nuclear factor NF-KB and interferon regulatory factor 3 (IRF3). Also dsRNA is detected by different sensors such as RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5), which they differ in their downstream signalling pathways and cellular localization (Vercammen et al., 2008).
TLR3 can be found at the cell surface or in endosomal compartments. The localization of TLR3 depends on the cell type, and that will reflect the participation of cell-type-specific pathways in antiviral Interferon (IFN) induction via TLR3. For example, Human fibroblasts express TLR3 on the cell surface, and anti-TLR3 monoclonal antibodies inhibit dsRNA-induced IFN-Î² secretion by fibroblasts. That suggests the TLR3 acts on the cell surface to sense viral infection in these cells. However, in most cell types, including DC, macrophages, and TLR3-transfected HEK293 cells, TLR3 is detected predominantly in intracellular compartments (Funami et al., 2004).
Viral dsRNA binds to the TLR3-CD14 complex; it induces the activation of several intracellular signalling pathways (Fig 1). The activation of NF-KB and IRF3 is achieved by two different signalling branches produced from the TLR3 adaptor molecule TRIF, which binds to the BB loop of the TLR3 Toll/Interleukin receptor (TIR) domain which play a key role in activating conserved cellular signal transduction pathways in response to bacterial LPS, microbial and viral pathogens, cytokines and growth factors. The binding of RIP1 to TRIF not only activates NF-KB but also recruits the death domain (DD) containing adaptor protein, Fas-Associated protein with death domain (FADD) via a homotypic DD-DD interaction. FADD in turn interacts with the cysteine protease procaspase-8 through the death effectors domain (DED) present in both proteins. This is believed to result in the proteolytic auto-activation of procaspase-8 and the initiation of cell death (Vercammen et al., 2008).
Study done by Jackson et al, shows that the TLR3 is also involved in the diseases of the central nervous system (CNS). The CNS generally consists of two main cell types: glial cells and neuronal cells. Glial cells are separated into micro-glial cells (CNS-resident innate immune cells) and macro-glial cells. When these cells have being triggered with dsRNA or viruses, such as rabies virus and herpes simplex virus type 1, they have been shown to express TLR3 and start the signalling pathway (Jackson et al., 2008).
Also the TLR3 was projected to have a defensive function during influenza A virus-induced encephalopathy, comparing to its destructive role in influenza A virus infection of the respiratory tract (Hidaka et al., 2006). Study shows that minor infection with West Nile virus of mice, TLR3-dependent inflammatory signalling was shown to ease viral entry into the brain, causing lethal encephalitis (Wang et al., 2004).
Figure 1: TLR3 signalling pathways (Adapted from Vercammen et al., 2008)
1.3 NOD-like receptors
The Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are a specialized group of intracellular receptors that represent a key component of the host innate immune system. in addition to their primary role in host defence against invading pathogens, their ability to regulate NF-ÎºB signalling, interleukin-1-beta (IL-1Î²) production, and cell death indicates that they are crucial to the pathogenesis of a variety of inflammatory human diseases (Chen et al., 2009).
Nod1 and Nod2 are intracellular proteins that are involved in recognition of bacterial molecules and their genetic variations have been linked to several inflammatory diseases that are strongly affected by environmental factors. However, the distribution of Nod1- and Nod2-stimulatory molecules in different bacterial species is unknown (Hasegawa et al., 2006). The signalling pathways through NOD-NLRs are regulated by caspase recruitment domain CARD-containing proteins (Geddes et al., 2009). NOD1 (CARD4) is widely expressed by many cell types and the expression of NOD2 (CARD15) is restricted to macrophages, dendritic cells, Paneth cells, keratinocytes and epithelial cells of the oral cavity, intestine and lung. NOD1 and NOD2 are both concerned in sensing the presence of bacterial peptidoglycan (PGN) fragments (Franchi et al., 2009). Nod1 senses mesodiaminopimelic acid (meso-DAP) containing peptidoglycan found in the cell wall of Gram-negative bacteria. On the other hand, Nod2 seems to be a general sensor which is activated by muramyl dipeptide (MDP), the minimal motif common to all PGNs of Gram-negative as well as Gram-positive bacteria (Takeda and Akira, 2005).
The recognition of MDP and DAP through leucine-rich repeat (LRR) domains activates the NOD2 and NOD1 proteins (fig 2). These then recruit receptor-interacting serine/threonine kinase (RICK) through caspase-recruitment domain (CARD) interactions. In the case of NOD2, activation of RICK leads to K63 (Lys63)-linked polyubiquitylation of IKKgamma, the scaffold of the inhibitor of NF-kappaB (IkappaB)-kinase complex (the IKK complex), which also consists of IKKalpha and IKKbeta. This is followed by the phosphorylation of IKKbeta, as well as the phosphorylation of IkappaB and the release of nuclear factor-kappaB (NF-kappaB) for translocation to the nucleus. In the case of NOD1, ubiquitylation of IKKgamma by RICK has not been studied, and the mechanism of NF-kappaB activation is not clear. CARD12 negatively regulates RICK-mediated NF-kappaB activation by both NOD1 and NOD2, whereas CARD6 negatively regulates only RICK-mediated NF-kappaB activation by NOD1 (for further details, see the main text). In addition to NF-kappaB activation, NOD1 and NOD2 signalling gives rise to the activation of mitogen-activated protein kinases (MAPKs) (Strober et al., 2006).
Figure 2: Signalling pathways of NOD1 and NOD2 (adapted from Strober et al., 2006)
2.0 Antimicrobial peptides (AMP)
2.1 Defensins and cathelicidins
The innate immune system contains hundreds of peptides, which have strong microbicidal activities at low concentrations. Antimicrobial peptides (AMP) are important components of the natural defenses of most living organisms. The two major families of mammalian antimicrobial peptides are defensins and cathelicidins (Boman, 2004).
Defensins and cathelicidins also are called the natural antibiotics. They are mainly produced by leukocytes and epithelial cells and found in Prokaryotes and Eukaryotes, also are produced in plants. These molecules were described in bacteria, invertebrates, vertebrates, also in mammals including humans (Witkowska et al., 2008).These AMP are secreted in large amounts in infected tissues, to provide an immediate early defence against infection. They have various protection actions against microorganisms, such as Gram-positive and Gram-negative bacteria, fungi and viruses (Klotman & Chang, 2006). The mechanisms of these antimicrobial action are complex and multiple and they have both indirect and direct antimicrobial activity, the ability to act as chemokines as well as induce chemokine production leading to recruitment of leukocytes to the site of infection, the promotion of wound healing and an ability to modulate adaptive immunity (Bowdish et al., 2006).
In mammals, the recently identify antimicrobial peptide Hepcidin, (a 25 amino acid peptide) is produced mainly by the liver. Hepcidin is iron-regulating hormone that is released during infection or in presence of high levels of iron in circulation. The release of Hepcidin in such circumstances has been a core point of study by scientists (Douglas et al., 2003)
Studies show that microorganisms require iron in order to survive and exert their virulence. These microorganisms have evolved complex mechanisms to extract iron from their environment. They produce complex molecular compounds called siderophores that bind any available iron for their utilization (Winkelmann, 2002). These molecules also extract iron from its storage sites such as ferritin and lactoferrin. The bound iron is transported into the bacterial cell via various transport mechanism such as the protein dependent transport complexes, PBTs (Faraldo-Gomez & Sansom, 2003).
It has been demonstrated that the PBTs act by leading the siderophore-associated iron to the ferric reductases on walls of the microbe. Furthermore, the PBTs internalize the siderophore-associated iron making it available for utilization by the pathogen. In the presence of Hepcidin all these iron, acquiring mechanisms by the microbe are inhibited and as such, Hepcidin has been appreciated to be a main component of the innate immune system in mammals (Ashrafian, 2003).
Further studies have shown that those microbes that fail to express siderophores for iron extraction, have reduced virulence. An example is the V. Vulnificus bacteria that do not express the catechol-derived siderophore. Consequently, it has reduced bacterial virulence as compared to the other bacteria in the same genus that express this type siderophore due to lack of iron (Weinberg 2000).
2.2.1 Iron regulation in the body
Iron is a constituent of all living matter. Iron is a core factor in electron transfer chain in the body; it is also a vital part of oxygen transport and iron storing molecules such as haemoglobin. It is also a component of host defence where it occurs in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Humans lack an effective mechanism to excrete surplus iron, though they are unsurpassed in iron conservation since they have unique homeostatic mechanisms that ensure iron level remains within normal parameters. These mechanisms regulate absorption of iron from the duodenum and release from macrophages and other iron storing sites (Anderson et al., 2007). Release of large amounts of iron into circulation may result in localized injury to the surrounding tissues. Iron exerts its toxic effects through catalysis of free radical reactions leading to production of free radicals such as peroxides that damage tissues. Furthermore, iron levels need to be maintained within physiological limits since infection is in part determined by availability of iron for utilization by the invading microorganism (Collins, 2003).
The liver is the centre of control of iron homeostasis in the body. Control of iron levels in the body is essential, since an overload results in organ damage and conditions like haemochromatosis. Deficiency of iron result in anaemia usually referred to as iron deficiency anaemia. The iron regulation process employs specialized sensors (Avunduk, 2008).
The connection between Hepcidin and iron overload was first brought to light by Pigeon et al during study of response of the liver to iron overload. (Pigeon et al., 2001). They found out that the Hepcidin mRNA was induced by iron overload of parenteral and dietary origin. Furthermore, they found out that induction of Hepcidin mRNA occurred when mice were treated with LPS to simulate an active bacterial infection. From these results, it was concluded, that Hepcidin production was under the influence of iron and an immune system stimuli (polysaccharide). It was also observed that the Hepcidin gene is in the same loci as the upstream regulatory factor-2(USF-2) gene. Other gene knock-out studies reinforced the relation between USF-2gene and iron overload, since mice that had their USF-2 gene knocked all developed haemochromatosis at the same time. (Nicholas et al., 2001). It was further observed that these mice had no Hepcidin mRNA expressed. This led the authors to conclude that Hepcidin was a controller of iron absorption from the duodenum and upper jejunum, and that it was a regulator of iron release from macrophages. It is the absence of Hepcidin that resulted in iron overload (haemochromatosis), since the gene coding for Hepcidin gene is located in the same loci as USF-2 gene.
2.2.2 Discovery of Hepcidin
Hepcidin was discovered when Park et al were conducting studies on antimicrobial characteristics of various fluids in the human body (Park et al., 2001). They extracted a new peptide from urine and named it Hepcidin based on its site of origin (hep- from hepatic) and its antimicrobial activity (-cidin; to kill). Krause et al working separately extracted a peptide with similar properties and referred to it as LEAP-1 (liver expressed antimicrobial peptide) which later on was found to be Hepcidin (Krause et al., 2000).
The Hepcidin mediated activities; iron regulation and antimicrobial activity are under the influence of one gene unlike in the mouse where we have two Hepcidin genes but only one code for iron regulation (Pigeon, 2001).
2.2.3 Importance of Hepcidin
Hepcidin is an essential component of the body's homeostasis process. It is the main regulator of iron homeostasis in the body. Furthermore, it plays a role in the innate immune system. Many iron disorders are as a result of abnormalities in Hepcidin production. Production of little amounts of Hepcidin causes iron overload in conditions like hereditary haemochromatosis and Î²-thalassemia a form of anaemia due to a defect in one of globin chains. On the other hand excessive production contributes to anaemia of inflammation initially called anaemia of chronic disease (ACD). In anaemia of inflammation, there is pronounced sequestration of iron in the macrophages while in thalassemia there is excessive breakdown of erythrocytes causing release of massive amounts of iron that may result in overload even in the absence of blood transfusions (Papanikolaou et al., 2005).
2.2.4 Effect of Iron on production Hepcidin
Homeostatic regulation of Hepcidin production is under the influence of iron levels and state of erythropoesis. Hepcidin production is up regulated when there is iron overload and down regulated in situations of iron deficiency. At the same time pronounced erythropoesis results in decreased production of Hepcidin to allow for increased absorption and release of iron from macrophages to meet the demands of the body. Production is also high in inflammatory conditions and infections. Although, precise mechanisms of regulation of production of Hepcidin have not been elucidated, it is widely believed that regulation is under the influence of factors released by the bone marrow. Such factors include the bone morphogenetic protein (BMP). This protein has been demonstrated to stimulate increased production of Hepcidin both in vitro and in in vivo (Xia et al., 2008). Several BMPs have been identified but BMP-6, has been repeatedly demonstrated to be the dominant regulator of Hepcidin production (Andriopoulos et al., 2009). Activation of BMP-6 occurs via co-receptors.
Hemojuvelin (HJV) has been identified to be the co-receptor that modulates BMP-6 activity. Mice that have HJV mutations develop iron overload without any other noticeable abnormality. Studies carried out in recent times have shown that in mice with iron overload there is an increased expression of the BMP-6 mRNA linking BMP-6 to be an indicator of amount of iron in the body. Some scientists have proposed that interfering with BMP-6 pathway may be of therapeutic value in cases of Hepcidin excess (Malyszko, 2009).
The transferrin receptor 2(TfR2) and haemochromatosis gene (HFE) are the iron level sensing genes and in hereditary haemochromatosis, these two are mutated. TfR2 is of hepatic origin, the source of Hepcidin. The iron-transferrin complex binds to TfR2 and stabilizes it. The new complex causes increased signal transduction of ERK1/2 and smad1/5/8 (Goswami & Andrews, 2006). HFE and iron transferrin share a site of association on TfR1 and when the levels of iron-transferrin complex are high, HFE is displaced from the site of association on TfR1. Despite the above, studies have repeatedly demonstrated that HFE and TfR2 play no role in iron regulation mediated by Hepcidin (Piperno et al., 2007,).
2.2.5 Effect of Erythropoesis on production
Elevated erythropoesis is a major inhibitor of Hepcidin production. A study carried out in mice showed a dose dependent decrease in expression of Hepcidin mRNA hours after they received a specified dose of erythropoietin. However, the effect of erythropoetin on production of Hepcidin is not well defined (Ashby et al., 2007). The mechanism by which erythropoesis inhibits Hepcidin production is not clearly understood. It has been postulated that proteins related to TGF-Î² super family are involved in this process. These proteins include growth differentiation factor 15 (GDF15) and twisted gastrulation protein (TWSG1). TWSG1 binds BMP-6 leading to suppression of expression of Hepcidin. This reinforces the theory that Hepcidin regulation is mediated via the BMP-6 pathway (Ashby et al., 2007).
These proteins were also detected in high levels in dyserythropoetic anaemia and Î²-thalassemias. The mechanism by which hypoxia suppresses Hepcidin production still remains to be determined.
2.2.6 Effect of inflammation on Hepcidin production
Inflammation is a potent stimulator of Hepcidin production. Studies have shown a rapid increase in levels of Hepcidin within onset of infection and inflammation in both mice and humans. Hepcidin decreases export of iron from macrophages hence depriving the microbes off iron, an essential component for survival of the microbe (Sharma et al., 2008). Inflammatory cytokines, specifically IL-6 mediate the up regulation in Hepcidin production (Nemeth et al., 2003). In inflammation hepcidin production is greatly increased. !00-fold increase of hepcidin was recorded during inflammation due to more virulent organisms. Small increases in production were observed when inflammation was due to less virulent microorganisms. Patients with sickle cell anaemia and myelodysplasia had a similar magnitude of hepcidin increase after they were transfused with fresh blood. Studies carried out in isolated human hepatocytes revealed an increase in hepcidin mRNA production when the hepatocytes were exposed to lipo-polysaccharide. This was evidence that hepcidin production was under influence of inflammation. This is explained as follows: the lipo-polysaccharide molecules interact with macrophages, in this case hepatic kuppfer cells. The kuppfer cells are activated to release cytokine messengers such as Interleukin-6(IL-6), a mediator of inflammatory response. IL-6 then induces hepcidin mRNA transcription and subsequent hepcidin production (Nemeth et al., 2003). From the above it is clear that hepcidin plays a major role in inflammation.
2.2.7 Hepcidin as an antimicrobial peptide
Hepcidin is composed of 25 amino acid residues with 4-disulfide bonds within its structure. It is a derivative of an 84-amino acid prepropetide produced in the liver. Other smaller Hepcidins with antimicrobial properties have also been isolated from human urine. These are the 20 and 22- amino acid residue Hepcidins. These Hepcidins have also been shown to have antimicrobial activity against a wide range of microbes. Hepcidin was named so in regard of its antimicrobial properties i.e. -cidin meaning to kill and hep-, in regard to its site of origin (Ganz & Nemeth, 2008).
Studies have shown that there is an increase in transcription and translation of Hepcidin mRNA during infection and inflammation. This led scientists to the theory that Hepcidin is an antimicrobial agent. Analogues of Hepcidin in other species have reinforced this phenomenon. An example is drosomycin, which is produced by the insect drosophila in its fatty layer (an equivalent of the liver in humans) during acute infections. Drosomycin acts as a defensin against bacterial infections in these insects. Other insect defensins exhibiting Hepcidin like activity include heliomicin and thanatin (Nemeth et al., 2003). Hepcidin is the equivalent of these insect defensins in humans.
In studies carried out Hepcidin demonstrated cidal activity against a wide range of microbes. Examples include Candida albicans, Aspergillus fumigatus, Aspergillus niger and antibacterial activity against both gram positives such as Staphylococcus aureus, Staphylococcus epidermidis, group B Streptococcus and gram negatives bacteria such as Escherichia coli ( Akarsu & Mamuk, 2007).
Hepcidin mRNA transcription is induced by liposaccharide(LPS) both in vivo and in vitro which is produced by invading microbes in the natural environment (Yang et al., 2000). Scientists have postulated that Hepcidin acts through binding on the cell wall surface of microbes. The antimicrobial activity is mediated by absence of iron for utilization by the invading organisms. When a microbe invades the host it initiates production of IL-6 which in turn amplifies transcription of Hepcidin mRNA. This leads to release of Hepcidin from hepatocytes into circulation. Circulating Hepcidin finds its way to the splenic macrophages, enterocytes and other iron containing cells where it binds to ferroportin an iron exporter inducing its internalization and subsequent degradation (Yang et al., 2000). As a result of this, iron export from these cells is impaired hence depriving the invading microbes off an essential component required for their survival.
Ferrportin is a571-amino acid protein that has an essential role in the exporting iron from cells into the plasma. Furthermore, it is the only known iron cellular exporter described to date. In the last few years, significant advances have been made in the understanding of how iron is exported from intracellular environment into the plasma, and how this process is regulated (Ganz, 2005).
It is further proposed that Hepcidin acts by penetrating invading cells through toll-like receptors and lead to accumulation of iron inside the microbe. When accumulated iron exceeds the level required by the microbe it becomes toxic to the microbe resulting in organ damage and death of microbes. Similarly transferrin an important iron transporter is closely related to lactoferrin, a potent iron chelator found on the surface of neutrophils and in secretions of the epithelium (De Domenico, 2007). Antimicrobial activity of lactoferrin is in part attributed to its iron chelation properties. Divalent metal trasporter 1(DMT1) is the main mechanism through which iron is absorbed across the intestinal wall. This transporter is analogous to Nramp 1, a cationic transporter found on the walls of macrophages. Mutations in the gene coding for this transporter eliminates the ability of macrophages to attack and destroy pathogens leading to an increased tendency of having infections (Forbes & Gros 2001).
2.2.8 Mechanism of action of Hepcidin
Inflammation and iron overload induce transcription of Hepcidin mRNA in the hepatocytes. Inflammatory mediators induce production of cytokines such as IL-1, IL-6, TNF-Î² and TNF-Î±. IL-6 acts by amplifying the transcription process. Hepcidin is produced in high amounts and released into circulation to be delivered to iron exporting cells located in the small intestine and spleen. Hepcidin then binds to the iron exporting protein called ferroportin (Fpn). When Hepcidin binds to ferroportin, it leads to activation of Jak2 pathway and subsequent phosphorylation of ferroportin. The phosphorylated receptor is turn internalized and degraded by the lysosome hence impairing iron export from the affected cell into circulation (De Domenico 2007) It has been established that in absence of iron overload and inflammation, macrophages have little ferroportin on their surface.
Figure 3: Mechanism of action of Hepcidin (Source: Ganz & Elizabeth 2008)
3.0 Anaemia of Inflammation
Anaemia of inflammation is associated with several conditions that are infectious, non-infectious or malignant in nature. It occurs when there is an infection due to bacterial microbes, viral and even yeasts. Anaemia of inflammation also occurs in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. Chronic diseases that have a slower course of progression such as, chronic kidney disease (CKD), liver failure, cancer and heart failure have been found to cause anaemia of inflammation as well as pro-inflammatory states such as aging (Weiss & Goodnough, 2005).
The phenomenon of anaemia of inflammation may be a protective mechanism by the body against infections from iron dependent microbes. In anaemia of inflammation, macrophages are devoid of iron, transferring saturation is at its lowest and there is a low level of iron in serum. In this type of anaemia, the bone marrow's response to erythropoietin (Epo) is diminished. This results in reduction of the lifespan of available red blood cells and increase in rate of breakdown of senescent ones in the spleen. This is a paradoxical occurrence since in anaemia of inflammation; the body aims to protect itself from the harmful effects of excess iron however, at the same time, the sequestration of iron results in shortened lifespan of the red blood cells (Roy & Andrews, 2005).
Most of these conditions are associated with production of cytokines such as IL-1, IL-6 and TNF Î± and Î². In this type of anaemia, iron levels in blood are decreased within 24 hours of onset of active infection. It has been postulated that the low blood levels of iron can be attributed to a shift of transferring-bound iron to the ferritin form which is not available for utilization by the body (Dallalio et al., 2003). IL-1 amplifies ferritin mRNA translation leading to production of large quantities of ferritin that bind iron. Cytokines such as IL-6 stimulate production of Hepcidin, an acute phase protein produced by the liver. Hepcidin is believed to decrease absorption of iron from the small intestine and release of iron from macrophages resulting in low iron levels observed in anaemia of inflammation. Studies show a strong correlation between levels of Hepcidin in urine and blood level of ferritin. Patients with anaemia of inflammation have high levels of Hepcidin in their urine in comparison with patients who have iron deficiency conditions (Means & Krantz 1992). Other cytokines such as TNF-Î± inhibit the expression of Hepcidin in mice and humans resulting in iron overload and hemochromatosis.
Hepcidin associates with its receptor, ferroportin on macrophages and enterocytes preventing them from releasing iron into circulation. When Hepcidin binds ferroportin, it initiates phosphorylation of ferroportin and subsequent uptake into lysosomes (internalization) where it undergoes degradation. This process is mediated via the JAK2 signal transduction pathway. As a result the iron exporter is not expressed on the surface of macrophages and duodenal enterocytes. Due to this, export of iron from these cells into general circulation is impaired and iron remains within these cells leading to hypoferremia. Ferroportin is the only transporter associated in export of iron from cells as a result it provides an essential target for agents that can be used in management of anemia of inflammation (Weinstein & Roy 2002).
Studies have also demonstrated a unique feature of erythrocytes in patients with anemia of inflammation. The erythrocytes in such patients have a shortened lifespan with a high turnover, though the iron released from their breakdown is sequestered by macrophages leading to a hypoferrimic state though iron is available within the body (Weiss & Goodnough, 2005)
In chronic conditions there is a large pool of cytokines in circulation and these cytokines induce proliferation of macrophages which in turn cause phagoytosis of the erythrocytes leading to anemia of inflammation. This action is mediated through cytokines like TNF-Î±, an inhibitor of Hepcidin transcription (Card, 2000).
Figure 4: The relation between cytokines and Hepcidin (adapted from Lankhorst & Wish 2009