title: Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia.
abstract: Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.
authors.affiliation: Department of Biochemistry, Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Armitage
authors.forename: Pei Jin
authors.initials: PJ
authors.lastname: Lim
authors.forename: Joe N
authors.initials: JN
authors.lastname: Frost
authors.forename: Sant-Rayn
authors.initials: SR
authors.lastname: Pasricha
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Soilleux
authors.forename: Emma
authors.initials: E
authors.lastname: Evans
authors.forename: Alireza
authors.initials: A
authors.lastname: Morovat
authors.forename: Ana
authors.initials: A
authors.lastname: Santos
authors.forename: Rebeca
authors.initials: R
authors.lastname: Diaz
authors.forename: Daniel
authors.initials: D
authors.lastname: Biggs
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davies
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
authors.forename: Samira
authors.initials: S
authors.lastname: Lakhal-Littleton
authors.forename: Hal
authors.initials: H
authors.lastname: Drakesmith
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D002003:Brucella abortus / Q000276:immunology*; D005838:Genotype; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology; D019189:Iron Metabolism Disorders / Q000276:immunology* / Q000382:microbiology; D055666:Lipopeptides / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D064451:Hepcidins; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D051193:Toll-Like Receptors