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A Commentary by Elizabeta Nemeth

Bessman et al. Dendritic cell-derived hepcidin promotes intestinal repair. Science. April 10, 2020.

The liver-derived hormone hepcidin regulates systemic iron homeostasis by occluding and causing the degradation of ferroportin on duodenal enterocytes that absorb dietary iron and on macrophages that recycle iron from old red blood cells. In recent years, however, generation of floxed-hepcidin mice has enabled conditional deletion of hepcidin in different cell types, and has revealed tissue-specific roles of the locally-produced hepcidin. Ablation of cardiomyocyte hepcidin led to cardiomyocyte iron deficiency, and contractile and metabolic dysfunction of the heart1. Ablation of hepcidin in macrophages, on the other hand, improved cardiac repair and regeneration in a model of acute myocardial infarction2. Ablation of hepcidin in keratinocytes worsened necrotizing fasciitis by impairing the recruitment of neutrophils3.

In a recent study published in Science by Bessman et al4 (also see the accompanying commentary5), the spectrum of local hepcidin roles was expanded to mucosal healing in a mouse model of inflammatory bowel disease (IBD). Surprisingly, it was the dendritic cells in the intestinal lamina propria of inflamed mice and human IBD patients that had elevated hepcidin expression. Ablation of hepcidin in these antigen-presenting cells in mice worsened the recovery from DSS-induced intestinal damage. Mice lost more weight, had disordered colon tissue architecture and shorter colon length compared to the control animals. Similarly impaired mucosal healing was observed in mice expressing hepcidin-resistant ferroportin in macrophages and neutrophils, suggesting that these cells are the targets of dendritic cell-derived hepcidin.

As to the mechanism by which hepcidin promotes mucosal healing, Bessman et al. show that hepcidin ablation in dendritic cells resulted in altered microbiota composition. This occurred in naïve mice (in the absence of the DSS insult), and in the absence of detectable iron changes in the gut. How the low levels of hepcidin production by dendritic cells in the absence of inflammation affect microbiota remains to be determined. However, fecal microbiota transplantation from the knockouts to germ-free wild-type mice recapitulated the impaired mucosal healing after DSS administration. This was partially attributed to the decreased abundance in the knockouts of the iron-sensitive Bifidobacterium species, which are known to protect the intestinal barrier. The authors hypothesized that in the absence of local hepcidin production during the DSS insult in KO mice, macrophage iron export increases, potentiated by enhanced recycling of RBCs due to local bleeding. This would result in higher extracellular iron concentration, and affect the growth of luminal and tissue-infiltrating bacteria. In support of this hypothesis, systemic administration of the iron chelator DFO improved mucosal healing in dendritic cell hepcidin KOs.

The article raises a number of important questions and therapeutic implications. Can hepcidin mimetics be used to improve mucosal healing in IBD? How does locally derived hepcidin in the absence of inflammation alter microbiota? Does hepcidin derived from dendritic cells play a role in other inflammatory conditions and in other tissues?

  1. Lakhal-Littleton S, Wolna M, Chung YJ, et al. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. Elife. 2016;5.
  2. Zlatanova I, Pinto C, Bonnin P, et al. Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury. Circulation. 2019;139(12):1530-1547.
  3. Malerba M, Louis S, Cuvellier S, et al. Epidermal hepcidin is required for neutrophil response to bacterial infection. J Clin Invest. 2020;130(1):329-334.
  4. Bessman NJ, Mathieu JRR, Renassia C, et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science. 2020;368(6487):186-189.
  5. Rescigno M. The “iron will” of the gut. Science. 2020;368(6487):129-130.

posted: August 12, 2020