Iron and intestinal immunity

Abstract

Purpose of review: Recent advances in the study of iron metabolism have led to a better understanding of the molecular basis for the interactions between iron and the inflammatory response. We will review this new information in the context of the gastrointestinal tract.

Recent findings: The effects of iron on microbial enteropathogens are well known. Recent work has demonstrated that iron also has potentially important effects on the intestinal microbiota. On the host side, hepcidin, a key regulator of mammalian iron metabolism, has emerged as an important mediator of the cross-talk between iron homeostasis and inflammation. Hepcidin-dependent changes in iron flux can influence the expression of inflammatory cytokines, and conversely, inflammatory cytokines can induce hepcidin expression and alter iron homeostasis. Hepcidin levels have been found to be elevated in some studies of inflammatory bowel disease, while manipulating hepcidin expression in animal models of this condition has beneficial effects on both inflammation and dysregulated iron metabolism.

Summary: The information on iron metabolism that has become available in recent years has shed new light on the pathogenesis of inflammatory diseases of the gastrointestinal tract, and is also starting to suggest new approaches to treating such diseases.

Figure 1

Mechanisms that regulate systemic iron homeostasis. Hepcidin is secreted by hepatocytes in response to signals that reflect iron status and inflammation. Iron overload and inflammatory cytokines such as IL-6 up-regulate hepcidin, while iron deficiency, anemia and hypoxia inhibit it. Hepcidin binds to the iron exporter ferroportin (FPN) on macrophages and duodenal enterocytes, leading to its internalization and degradation.

Figure 2

Mechanisms that regulate cellular iron homeostasis. Iron-responsive elements (IREs) are present in the 5’ or 3’ untranslated regions of mRNAs encoding ferroportin (FPN) and ferritin or the type 1 transferrin receptor (TfR1) and Nramp2, respectively. They are bound by iron-regulatory proteins (IRPs) under low iron conditions, leading to either inhibition of translation or stabilization of the transcript. When cellular iron levels are high, these effects are reversed as a result of decreased IRE-IRP binding.