Iron homeostasis and the inflammatory response

Abstract

Iron and its homeostasis are intimately tied to the inflammatory response. The adaptation to iron deficiency, which confers resistance to infection and improves the inflammatory condition, underlies what is probably the most obvious link: the anemia of inflammation or chronic disease. A large number of stimulatory inputs must be integrated to tightly control iron homeostasis during the inflammatory response. In order to understand the pathways of iron trafficking and how they are regulated, this article presents a brief overview of iron homeostasis. A major focus is on the regulation of the peptide hormone hepcidin during the inflammatory response and how its function contributes to the process of iron withdrawal. The review also summarizes new and emerging information about other iron metabolic regulators and effectors that contribute to the inflammatory response. Potential benefits of treatment to ameliorate the hypoferremic condition promoted by inflammation are also considered.

Figure 1. Regulators of hepcidin synthesis during inflammation

Activation of STAT1/3 by cytokine signaling promotes transcription through a STAT element. IL-6 plays a predominant role in this inflammatory response. This element appears to be regulated through the nearby BMP-RE1 via SMAD activation, which is required for full promoter activity. A distal BMP-RE2 site is thought interact with the SMAD/STAT complex that brings distal and proximal regions of the hepcidin promoter into physical contact. SMAD signaling is activated through the HJV/BMP pathway. HJV is negatively regulated by matripase-2 cleavage; BMP signaling is negatively regulated by GDF15 and TWSG1. HFE interacts with TfR1 and may be released upon binding of diferric Tf. While binding of both diferric Tf and HFE to the TfR2 are known to stimulate hepcidin synthesis, the molecular aspects of this pathway remain unknown. In addition, ER stress response pathways involved in inflammation are known to induce hepcidin through at least two mechanisms: 1) negative regulation of C/EBPα by CHOP and 2) activation of CREBH, possibly in conjunction with activated (spliced) XBP-1.