Iron Regulatory Protein 1 is Required for the Propagation of Inflammation in Inflammatory Bowel Disease

Abstract

ObjectiveInflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. DesignThis study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. ResultsWe found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. ConclusionThese findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD. What is already known on this topicInflammatory bowel diseases (IBD) are chronic conditions that cause inflammation in the digestive tract. Iron accumulation is a common feature of IBD, but the mechanism of accumulation and its implications for the course of inflammation are not fully understood. What this study addsThis study reveals an inflammatory intestinal iron distribution-pattern, that has not been described previously involving iron accumulation in immune cells and iron deficiency in epithelial cells. We show that an inflammation mediated activation of the Iron Regulatory Protein (IRP)1 is responsible for this inflammatory iron pattern and that this drives the propagation of the inflammation in IBD. Moreover, targeted deletion of IRP1 completely abolished the intestinal inflammation. How this study might affect research, practice or policyThese findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa in IBD. This might lead to the development of novel treatment approaches for IBD focused on modulating IRP1 activity.