TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens.
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.
Peyssonnaux
Carole
C
Division of Pediatric Infectious Diseases, Cellular and Molecular Medicine East, Rm 1066, University of California at San Diego School of Medicine, 9500 Gilman Dr, MC 0687, La Jolla, 92093-0687, USA.
Zinkernagel
Annelies S
AS
Datta
Vivekanand
V
Lauth
Xavier
X
Johnson
Randall S
RS
Nizet
Victor
V
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics; D001424:Bacterial Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027682:Cation Transport Proteins / Q000378:metabolism; D015870:Gene Expression; D064451:Hepcidins; D066298:In Vitro Techniques; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009504:Neutrophils / Q000378:metabolism* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000472:pathogenicity; D013297:Streptococcus pyogenes / Q000472:pathogenicity; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000098742:Ferroportin