Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload†

Montosi, Giuliana; Corradini, Elena; Garuti, Cinzia; Barelli, S.; Recalcati, Stefania; Cairo, Gaetano; Valli, Linda; Pignatti, Elisa; Vecchi, Chiara; Ferrara, Francesca; Pietrangelo, Antonello

doi:10.1002/hep.20620

Cited by 63 publications

(53 citation statements)

References 30 publications

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“…40 The role of Kupffer cells in inflammatory activation of hepcidin remains controversial. 40,41 Our finding that iron treatment functioned to suppress rather than stimulate macrophage hepcidin production suggests that myeloid cells do not themselves contribute to the elevated hepcidin levels characteristic of iron overload conditions in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study excluded liver reticuloendothelial macrophages (eg, Kupffer cells) for this function, as adminstration of gadolinium (III) chloride to inhibit Kupffer cells phagocytosis and activation did not affect hepatic hepcidin activation during iron overload. 40 The role of Kupffer cells in inflammatory activation of hepcidin remains controversial. 40,41 Our finding that iron treatment functioned to suppress rather than stimulate macrophage hepcidin production suggests that myeloid cells do not themselves contribute to the elevated hepcidin levels characteristic of iron overload conditions in vivo.…”

Section: Discussionmentioning

confidence: 99%

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TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens

Peyssonnaux

Zinkernagel

Datta

et al. 2006

Blood

329

243

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Hepcidin is an antimicrobial peptide secreted by the liver during inflammation that plays a central role in mammalian iron homeostasis. Here we demonstrate the endogenous expression of hepcidin by macrophages and neutrophils in vitro and in vivo. These myeloid cell types produced hepcidin in response to bacterial pathogens in a toll-like receptor 4 (TLR4)-dependent fashion. Conversely, bacterial stimulation of macrophages triggered a TLR4-dependent reduction in the iron exporter ferroportin. In vivo, intraperitoneal challenge with Pseudomonas aeruginosa induced TLR4-dependent hepcidin expression and iron deposition in splenic macrophages, findings mirrored in subcutaneous infection with group A Streptococcus where hepcidin induction was further observed in neutrophils migrating to the tissue site of infection. Hepcidin expression in cultured hepatocytes or in the livers of mice infected with bacteria was independent of TLR4, suggesting the TLR4-hepcidin pathway is restricted to myeloid cell types. Our findings identify endogenous myeloid cell hepcidin production as a previously unrecognized component of the host response to bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens

Peyssonnaux

Zinkernagel

Datta

et al. 2006

Blood

329

243

View full text Add to dashboard Cite

show abstract

“…13,[38][39][40][41][42][43][44] Most studies to date have shown that the transcriptional changes in the Hepc gene expression parallel the changes in serum iron concentration; however, limited studies have been performed to show the changes in the concentration of this important hormone in the serum. [45][46][47][48] Intramuscular TO injection induced significant decrease of the serum iron concentration without a significant change in serum proHepc concentration. One possible explanation for no significant change in serum concentration of Hepc could be that Northern blot analysis of total RNA extracted from different organs of the TO-injected rats taken at different time points (Materials and methods).…”

Section: Discussionmentioning

confidence: 99%

Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat

Sheikh

Dudás

Ramadori

2007

Laboratory Investigation

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“…28 In a separate experiment, rats were injected intraperitoneally with 0.1 mg/g body weight of zymosan. 29 C3H/HeJ mice were treated with similar doses of GD and zymosan by an IP injection.…”

Section: Gd and Zymosan Treatment Of Rats And C3h/hejmentioning

confidence: 99%

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi

Ahmad

Ramadori

et al. 2009

Laboratory Investigation

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The liver and the spleen are the organs in which cellular material and aged erythrocytes are eliminated from the blood. Within the liver, Kupffer cells (KCs) are mainly responsible for this task, as such KCs have a pivotal role in iron metabolism. The aim of this study is to investigate the changes of hepatic gene expression in two models of KC phagocytosis. Gadolinium chloride (GD) or zymosan was injected intraperitoneally into rats and to endotoxin-resistant mice (C3H/HeJ). The animals were killed at different time points and their livers were immediately frozen in liquid nitrogen for RNA isolation and immunohistological studies. RNA was analyzed by real-time PCR and northern blot. Sera were used to measure transaminases, hepcidin and iron levels. The expression of iron metabolism genes, hepcidin, hemojuvelin (Hjv), ferroportin-1 (Fpn-1) and of the inflammatory cytokines IL-6, IL-1b, TNF-a and IFN-g was determined. Although phagocytosed material was detected in ED-1-and C1q-positive cells, no inflammatory cells were identified within the liver parenchyma. Serum levels of hepcidin, iron and transaminases did not differ from those of control animals. Both GD and zymosan induced an upregulation of hepcidin-gene expression in rat liver as early as 3 h, reaching a maximum 6 h after treatment. Hjv-and Fpn-1-gene expression was downregulated at the same time. IL-6 was by far the most induced acute-phase-cytokine in GD-and zymosan-treated livers, although IL-1b and TNF-a were also strongly upregulated by zymosan and to a lesser extent by GD. Similar results were obtained in the C3H/HeJ mouse strain excluding the possible role of contaminating endotoxin. This study shows that phagocytosis upregulates hepcidin-gene expression and downregulates Hjv-and Fpn-1-gene expression within the liver. These changes in iron-regulating-gene expression may be mediated by the locally produced acute-phase-cytokines.

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Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload†

Cited by 63 publications

References 30 publications

TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens

TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens

Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

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