An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice

Abstract

Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia1. Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone2,3 that inhibits duodenal iron absorption and macrophage iron release4,5,6,7. Hamp is part of the type II acute phase response8 and is thought to have a crucial regulatory role in sequestering iron in the context of ACD7,9. Mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggest a previously unidentified role for Hfe in innate immunity and ACD.