title: Low hepcidin accounts for the proinflammatory status associated with iron deficiency.
abstract: Hepcidin is an antimicrobial peptide that controls systemic iron homeostasis. Hepcidin binding to its receptor ferroportin reduces iron availability, thus controlling microbial growth. In parallel it triggers an anti-inflammatory response in macrophages. Hepcidin is transcriptionally regulated by iron, through the bone morphogenetic protein-son of mothers against decapentaplegic (BMP-SMAD) pathway and by inflammation, through IL6-mediated STAT3 signaling. To investigate the mechanisms linking iron and inflammation, we treated C57BL/6 iron-deficient mice with a sublethal dose of lipopolysaccharide (LPS) and analyzed their inflammatory response in comparison with controls. We show that iron-deprived mice have a proinflammatory condition, exacerbated by LPS treatment leading to increased IL6 and TNFα mRNA in liver and spleen macrophages, and increased serum IL6 (482.29 ± 205.59 pg/mL) versus controls (69.01 ± 17.52 pg/mL; P < .05). Hepcidin was undetectable in iron-deficient mice but pretreatment with hepcidin normalized their response to LPS. Tmprss6(-/-) mice, characterized by iron deficiency and high hepcidin, show a blunted inflammatory response when challenged with LPS. Our data support a model in which the lack of hepcidin is responsible of the high inflammatory response to LPS in iron deficiency. The proinflammatory status associated with chronic iron deficiency could explain the resistance to infection seen in this condition.
authors.affiliation: Vita-Salute San Raffaele University and Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Pagani
authors.forename: Antonella
authors.initials: A
authors.lastname: Nai
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Corna
authors.forename: Lidia
authors.initials: L
authors.lastname: Bosurgi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
authors.forename: Laura
authors.initials: L
authors.lastname: Silvestri
mesh_terms: D000210:Acute-Phase Reaction / Q000276:immunology / Q000378:metabolism; D018798:Anemia, Iron-Deficiency / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000276:immunology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D064451:Hepcidins; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D007501:Iron / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051785:Smad Proteins / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics
chemical_list: D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007501:Iron; D012697:Serine Endopeptidases; C467801:matriptase 2