Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia.

Armitage, Andrew E, Lim, Pei Jin, Frost, Joe N, Pasricha, Sant-Rayn, Soilleux, Elizabeth J, Evans, Emma, Morovat, Alireza, Santos, Ana, Diaz, Rebeca, Biggs, Daniel, Davies, Benjamin, Gileadi, Uzi, Robbins, Peter A, Lakhal-Littleton, Samira and Drakesmith, Hal (2016) Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia. Journal of innate immunity, 8 (5). pp. 517-28. ISSN 1662-8128.

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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.

Item Type: Article
Subjects: QW Microbiology. Immunology
QY Clinical pathology
Divisions: Clinical Support > Pathology
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Depositing User: Preeti Puligari
Date Deposited: 06 Mar 2017 15:44
Last Modified: 06 Mar 2017 15:44

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