Inflammation-induced up-regulation of hepcidin and down-regulation of ferroportin transcription are dependent on macrophage polarization.
Iron is essential in all organisms. In mammals systemic iron homeostasis relies on hepcidin, a peptide hormone with defensin properties, and its target, the cell iron exporter ferroportin. Hepcidin and ferroportin transcription are both upregulated by high iron levels, but are inversely regulated upon inflammation, leading to hypoferremia. Thus, host iron genes regulation may affect the innate immune responses against infectious microorganisms. Since macrophages, which are crucial innate immune cells, express both hepcidin and ferroportin, we explored in these cells their transcriptional regulation upon inflammation which is not completely understood. Macrophages represent an heterogenous population of immune cells resulting from cytokine and pathogen sensing, indeed macrophages polarized especially into pro-inflammatory M1 and regulatory/anti-inflammatory M2 phenotypes. We found that hepcidin mRNA upregulation depends on M1 polarization and ferroportin mRNA downregulation depends on M2 subtype polarization. All TLR agonists, except TLR2 agonist, polarize to pro-inflammatory macrophages and upregulate hepcidin mRNA expression. Cell pretreatment with IFNγ or inhibitor of PI3K, p38-MAPK and NF-κB pathway involved in M1 polarization prior TLR4 activation, enhanced hepcidin upregulation. Conversely, ferroportin mRNA downregulation upon inflammation was strongly increased by macrophage polarization through TLR2- and 4-PI3K-dependent pathways, or through IL-1β and TNFα priming prior to LPS activation.
Experimental and Molecular Immunology and Neurogenetics, UMR 7355 CNRS, 3B rue de la Ferollerie, 45071 Orléans, France; University of Orléans, Orléans, France. Electronic address: rafiou.agoro@cnrs-orleans.fr.
Rafiou
R
Agoro
Experimental and Molecular Immunology and Neurogenetics, UMR 7355 CNRS, 3B rue de la Ferollerie, 45071 Orléans, France; University of Orléans, Orléans, France. Electronic address: catherine.mura@cnrs-orleans.fr.
Catherine
C
Mura
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D027682:Cation Transport Proteins / Q000235:genetics*; D016764:Cell Polarity; D005786:Gene Expression Regulation / Q000276:immunology*; D064451:Hepcidins / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000166:cytology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D017737:Macrophages, Peritoneal; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000098742:Ferroportin
D027682:Cation Transport Proteins; D064451:Hepcidins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000098742:Ferroportin; D019869:Phosphatidylinositol 3-Kinases
Ferroportin; Hepcidin; Inflammation; Macrophage polarization