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

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 <i>(Hamp1)</i> is the master regulator of iron and its expression is induced by inflammation. Mice lacking <i>Hamp1</i> from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as <i>Vibrio vulnificus</i>. 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 <i>Hamp1</i> deletion (termed i<i>Hamp1</i>-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. <i>Hamp1</i> 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 <i>Brucella abortus</i> caused an equivalent induction of inflammation in control and i<i>Hamp1</i>-KO mice. Pam3CSK4 and <i>B. abortus</i> only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in i<i>Hamp1</i>-KO mice<i>. </i>Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.