Abstract
Hepcidin belongs to the antimicrobial peptide (AMP) family and is the key regulator of iron metabolism. It modulates iron homeostasis by binding to, and degrading the iron exporter molecule, ferroportin, thus inhibiting cellular iron efflux. Many antimicrobial peptides have a dual function; some are able to act directly as an antimicrobial agent as well as having an immunoregulatory role in the host. Toll-like receptors (TLRs) bind to components of microorganisms, activate cellular signal transduction pathways and stimulate innate immune responses. The effect of TLR3 (poly I:C) and TLR9 (CpG) co-stimulation of THP-1-derived monocytes using purified TLR ligands showed that 24h after exposure poly I:C and CpG ligands in combination, hepcidin expression was significantly increased (10-fold) when compared to the untreated control. This combination of TLR ligands mimics simultaneous bacterial and viral infections, thus suggesting a potential key role for hepcidin in combined infections. Additionally, using a chequerboard assay, we have shown that hepcidin has an antagonistic effect in combination with the antibiotics rifampicin and tetracycline against Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes, evidenced by a fractional inhibitory concentration index (FICI)>4. This finding has important implications for future treatment regimens especially in an era of increasing antimicrobial resistance.
Highlights
Iron is required by most life forms because it is involved in many cellular and metabolic processes
Co- stimulation of THP-1 cells with CpG and polycytidylic acid (Poly I):C induces hepcidin expression Poly I:C is a synthetic analog of double-stranded RNA, a molecular pattern associated with viral infection
CpG ODNs are synthetic oligonucleotides that contain unmethylated CpG dinucleotides in particular sequence contexts (CpG motifs). These CpG motifs are present in bacterial DNA and are recognized by Toll-like receptor 9 (TLR9) which induces strong immunostimulatory effects
Summary
Iron is required by most life forms because it is involved in many cellular and metabolic processes. Hepcidin was first documented in 2001 (Park et al, 2001) and it has since been described as the principal regulator of iron homeostasis. Hepcidin binds to the only known mammalian iron exporter molecule, ferroportin, and this binding causes the internalization and degradation of the hepcidinferroportin complex (Weinstein et al, 2002; and Rodriguez et al 2014). Ferroportin is highly expressed on duodenal enterocytes and macrophages; when hepcidin levels are raised such as in time of infection or inflammation, both dietary iron uptake and recycling of iron from senescent red blood cells by macrophages are reduced. Hepcidin levels that are persistently elevated in conditions such as chronic infection or inflammation, can lead to iron redistribution into the reticuloendothelial system, causing anaemia due to the reduced supply of iron to the bone marrow for erythropoiesis (Nicholas et al, 2001; Roetto et al, 2003)
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