Role of Par2 and macrophages in hepcidin regulation

During erythropoietic stress, inhibition of hepcidin increases the bioavailability of iron in parallel to hemoglobin synthesis. The secretion of erythroferrone by erythroblastic progenitors and the production of the hepatokine Fgl1 have previously been implicated in hepcidin suppression. However, we have observed that, in addition to these factors, suppression of hepcidin in response to erythroid stress is also dependent on PAR2, a protease-activated receptor.



In this study, we highlight the role of PAR2 in regulating hepcidin under conditions of erythroid stress. First, we observed that Par2-/- embryos are anemic. Then, to investigate its role in hepcidin suppression, we phlebotomized Par2-/- mice and analyzed hepcidin expression 48 hours later. We observed that Par2 deletion prevents the suppression of hepcidin. Since Par2 is not expressed in hepatocytes, we suspected a role in another cell type. Given that Par2 plays an important role in macrophages, we generated mice with a specific deletion of Par2 in macrophages by crossing Par2-floxed mice with LysM-cre mice and subjected them to phlebotomy. Similarly, to Par2-/- mice, Par2 deletion in macrophages prevents hepcidin suppression. We then questioned the essential role of macrophages in erythroid stress-dependent hepcidin suppression using mice expressing the diphtheria toxin receptor only in macrophages (LysM cre iDTR). In this mouse model, when macrophages are depleted hepcidin is not suppressed in response to phlebotomy. These data highlight a new role of macrophages in the regulation of hepcidin.



We are now characterizing the roles of macrophages and Par2 in this cell type in the regulation of hepcidin.