Response of Monocyte Iron Regulatory Protein Activity to Inflammation: Abnormal Behavior in Genetic Hemochromatosis

Abstract

In genetic hemochromatosis (GH), iron overload affects mainly parenchymal cells, whereas little iron is found in reticuloendothelial (RE) cells. We previously found that RE cells from GH patients had an inappropriately high activity of iron regulatory protein (IRP), the key regulator of intracellular iron homeostasis. Elevated IRP should reflect a reduction of the iron pool, possibly because of a failure to retain iron. A defect in iron handling by RE cells that results in a lack of feedback regulation of intestinal absorption might be the basic abnormality in GH. To further investigate the capacity of iron retention in RE cells of GH patients, we used inflammation as a model system as it is characterized by a block of iron release from macrophages. We analyzed the iron status of RE cells by assaying IRP activity and ferritin content after 4, 8, and 24 hours of incubation with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). RNA-bandshift assays showed that in monocytes and macrophages from 16 control subjects, IRP activity was transiently elevated 4 hours after treatment with LPS and IFN-γ but remarkably downregulated thereafter. Treatment with NO donors produced the same effects whereas an inducible Nitric Oxide Synthase (iNOS) inhibitor prevented them, which suggests that the NO pathway was involved. Decreased IRP activity was also found in monocytes from eight patients with inflammation. Interestingly, no late decrease of IRP activity was detected in cytokine-treated RE cells from 12 GH patients. Ferritin content was increased 24 hours after treatment in monocytes from normal subjects but not in monocytes from GH patients. The lack of downregulation of IRP activity under inflammatory conditions seems to confirm that the control of iron release from RE cells is defective in GH.

The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellularSalmonella typhimurium

“…The host defence directed against intracellular pathogens such as Salmonellae strongly depends on IFN-gdriven macrophage immune effector pathways which are regulated by the intraphagocyte iron content. While a minimum amount of iron is required for the generation of toxic oxygen species by phox (Collins et al, 2002), macrophage iron overload inhibits the transcription of iNOS and thus the generation of NO (Weiss et al, 1994;Dlaska and Weiss, 1999), the formation of TNF-a and antigen presentation via MHC II (Recalcati et al, 1998;Oexle et al, 2003).…”

“…Iron is a critical determinant in host-pathogen interplay because it affects cell-mediated immune pathways while also representing an essential nutrient for microbes (Weinberg, 1992;Weiss, 2002). Iron exerts an inhibitory effect towards interferon-g (IFN-g) activity, which negatively affects antimicrobial effector pathways of macrophages including the expression of inducible nitric oxide synthase (iNOS) and of tumour necrosis factor-a (TNF-a) (Weiss et al, 1994;Recalcati et al, 1998;Oexle et al, 2003). Importantly, the expression of iron acquisition systems by pathogens has been linked to their pathogenicity and is essential for microbial growth and proliferation (Boyer et al, 2002;Schrettl et al, 2004).…”

Hereditary hemochromatosis results in decreased iron acquisition and growth byMycobacterium tuberculosiswithin human macrophages

“…In contrast to most other types of cells where hereditary hemochromatosis leads to Fe overload, reticuloendothelial macrophages and monocytes from individuals with hereditary hemochromatosis exhibit decreased intracellular Fe levels due to excessive Fe efflux relative to cells from healthy control subjects [22][23][24][25]. In previous work, we demonstrated that M.tb cultured in monocyte-derived macrophages (MDM) from individuals with hereditary hemochromatosis acquire significantly less Fe from Tf than MDM from normal subjects [26].…”

“…Our previous studies have shown that M.tb residing within MDM from subjects with hemochromatosis acquire less Fe from Tf than bacilli located in MDM from healthy control subjects [26]. This could be related to alterations in TfR function or to the decrease in the labile pool of Fe in the macrophage cytoplasm that has been shown to occur in these cells [22][23][24][25]. To address these two possibilities, we examined whether there is a difference in Fe acquisition from Lf, by intraphagosmal M.tb residing within MDM derived from individuals with hereditary hemochromatosis relative to those from healthy control subjects.…”

“…In vitro studies of the Fe metabolism of macrophages from individuals with hereditary hemochromatosis have focused on Fe from Tf [23,24,37]. To what extent mutations in HFE could impact macrophage Fe acquisition from Lf has not been extensively examined.…”