Systemic
iron balance is controlled by
hepcidin, a liver
hormone that limits
iron efflux to the bloodstream by promoting degradation of the
iron exporter
ferroportin in target cells.
Iron-dependent
hepcidin induction requires hemojuvelin (HJV), a
bone morphogenetic protein (BMP) coreceptor that is disrupted in
juvenile hemochromatosis, causing dramatic
hepcidin deficiency and tissue
iron overload. Hjv-/- mice recapitulate phenotypic hallmarks of
hemochromatosis but exhibit blunted
hepcidin induction following
lipopolysaccharide (LPS) administration. We show that Hjv-/- mice fail to mount an appropriate hypoferremic response to acute
inflammation caused by LPS, the
lipopeptide FSL1, or
Escherichia coli infection because residual
hepcidin does not suffice to drastically decrease macrophage
ferroportin levels. Hfe-/- mice, a model of milder
hemochromatosis, exhibit almost wild-type inflammatory
hepcidin expression and associated effects, whereas double Hjv-/-Hfe-/- mice phenocopy single Hjv-/- counterparts. In primary murine hepatocytes, Hjv deficiency does not affect
interleukin-6 (IL-6)/Stat, and only slightly inhibits BMP2/Smad signaling to
hepcidin; however, it severely impairs BMP6/Smad signaling and thereby abolishes synergism with the IL-6/Stat pathway. Inflammatory induction of
hepcidin is suppressed in
iron-deficient wild-type mice and recovers after the animals are provided overnight access to an
iron-rich diet. We conclude that Hjv is required for inflammatory induction of
hepcidin and controls the acute hypoferremic response by maintaining a threshold of Bmp6/Smad signaling. Our data highlight Hjv as a potential pharmacological target against
anemia of
inflammation.