Immune regulation of tissue iron in health and disease

PROJECT ABSTRACT Anemia and inflammation often co-occur in chronic diseases including inflammatory bowel disease (IBD), infection, and cancer. Anemia is often refractory to treatment in these diseases, and the impact of anemia and anemia therapies on disease outcome is poorly defined. Accordingly, there is a significant medical need to better understand the causal links between anemia and inflammatory diseases. One of the best defined links between anemia and inflammation is a peptide hormone called hepcidin, which critically inhibits iron release from intracellular stores. Hepcidin levels typically increase dramatically during inflammation, and can cause one form of anemia termed anemia of inflammation (AI). Conversely, inflammatory diseases associated with heavy bleeding cause a distinct form of anemia known as iron deficiency anemia (IDA), in which hepcidin levels are suppressed. The fundamental focus of this research proposal is to: i.) investigate the impact of hepcidin on inflammatory disease, ii.) identify cellular populations expressing hepcidin and its partner ferroportin during inflammation, and iii.) determine the impact of iron modulation by distinct cellular population on the resolution of inflammatory diseases. I will employ innovative technical approaches and develop new tools to define the role of hepcidin and ferroportin during chemically-induced intestinal damage, intestinal infection, and in inflammation-induced cancer. Collectively, results from these studies will define the regulation and functional significance of novel cellular mediators of iron within the intestine. These findings will critically inform ongoing efforts to develop therapies targeting tissue repair and anemia in the context of inflammatory diseases.