Apoptotic cell removal in development and tissue homeostasis

Cell deletion is a physiological process for the development and maintenance of tissue homeostasis in metazoa. This is mainly achieved by the induction of various forms of programmed cell death followed by the recognition and removal of the targeted cells by phagocytes. In this review, we will discuss cell deletion in relation to the development and function of the innate immune system, particularly of the mononuclear phagocyte system (MPS), its ontogeny and potential role in tissue remodeling in the embryo and adult. Ongoing studies are addressing the roles of professional phagocytes of the MPS and neighboring tissue cells in dying cell removal, and candidate molecules that might attract mononuclear phagocytes to the dying cells. The potential phagocyte must discriminate between living and dying cells; current concepts for this discrimination derive from the observation of newly exposed ligands on the dying cells and new evidence for direct inhibition of uptake by viable cells.

Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency

Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (~50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (~60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to ~40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.