title: Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells.
abstract: Inflammation and iron accumulation are present in a variety of neurodegenerative diseases that include Alzheimer's disease and Parkinson's disease. The study of the putative association between inflammation and iron accumulation in central nervous system cells is relevant to understand the contribution of these processes to the progression of neuronal death. In this study, we analyzed the effects of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) and of lipopolysaccharide on total cell iron content and on the expression and abundance of the iron transporters divalent metal transporter 1 (DMT1) and Ferroportin 1 (FPN1) in neurons, astrocytes and microglia obtained from rat brain. Considering previous reports indicating that inflammatory stimuli induce the systemic synthesis of the master iron regulator hepcidin, we identified brain cells that produce hepcidin in response to inflammatory stimuli, as well as hepcidin-target cells. We found that inflammatory stimuli increased the expression of DMT1 in neurons, astrocytes, and microglia. Inflammatory stimuli also induced the expression of hepcidin in astrocytes and microglia, but not in neurons. Incubation with hepcidin decreased the expression of FPN1 in the three cell types. The net result of these changes was increased iron accumulation in neurons and microglia but not in astrocytes. The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin. This connection may potentially contribute to the progression of neurodegenerative diseases by enhancing iron-induced oxidative damage.
authors.affiliation: Department of Biology, Faculty of Sciences, Universidad de Chile and Research Ring on Oxidative Stress in the Nervous System, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Urrutia
authors.forename: Pabla
authors.initials: P
authors.lastname: Aguirre
authors.forename: Andrés
authors.initials: A
authors.lastname: Esparza
authors.forename: Victoria
authors.initials: V
authors.lastname: Tapia
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Mena
authors.forename: Miguel
authors.initials: M
authors.lastname: Arredondo
authors.forename: Christian
authors.initials: C
authors.lastname: González-Billault
authors.forename: Marco T
authors.initials: MT
authors.lastname: Núñez
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000276:immunology; D027682:Cation Transport Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000166:cytology; D064451:Hepcidins; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D015850:Interleukin-6; D007501:Iron; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C578703:Hamp protein, rat
keywords: DMT1; FPN1; hepcidin; inflammation; iron accumulation; neurodegeneration