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

Abstract

Inflammatory bowel diseases (IBD) are complex disorders characterized by a cycle of inflammatory perpetuation. 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. This study addresses the role of iron homeostasis in IBD using human biopsies, animal models and cellular systems. It demonstrates inflammation-mediated modifications of iron homeostasis, and an 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 reproduced the iron-pattern observed in vivo. Importantly, deletion of IRP1 from an IBD mouse model completely abolished mis-distribution of iron and intestinal inflammation, suggesting a central role of IRP1 in the coordination of inflammatory response in the intestinal mucosa. Thus, this work identifies IRP1 as a target for IBD treatment.

The Role of Fractalkine in the Regulation of Endometrial Iron Metabolism in Iron Deficiency

“…IRP1 activity is known to be increased in iron deficiency, which triggers iron uptake [ 44 ]. In the meantime, it can be elevated in an iron-independent way, via the inflammatory response mediated by the NFκB signaling pathway [ 45 ]. Despite the aforementioned observations, a strong inhibitory effect of FKN on iron uptake protein levels was revealed at 48 h DFO treatment in the presence of serum.…”

“…Although FKN provided a positive impact on the FTH level compared to the DFO treatment, which suggests that FKN acts as a modulator of FTH synthesis, these levels would not be able to reach the FTH level of the control cells. It cannot be ruled out that FKN provokes IRP1 activity via the NFκB pathway, which in turn stabilizes and promotes FTH translation [ 45 ].…”