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Hepcidin-mediated hypoferremic response to acute inflammation requires a threshold of Bmp6/Hjv/Smad signaling

Carine Fillebeen, Nicole Wilkinson, Edouard Charlebois, Angeliki Katsarou, John Wagner and Kostas Pantopoulos

Key Points

  • Hjv−/− mice fail to mount an appropriate hypoferremic response to acute inflammation.

  • Hjv promotes inflammatory hypoferremia by maintaining a threshold of Bmp6/Smad signaling to hepcidin in hepatocytes.

Abstract

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.

  • Submitted March 23, 2018.
  • Accepted September 11, 2018.
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