title: Toll-like receptor signal adaptor protein MyD88 is required for sustained endotoxin-induced acute hypoferremic response in mice.
abstract: Hypoferremia, associated with immune system activation, involves a marked reduction in the levels of circulating iron, coupled with iron sequestration within macrophages. Toll-like receptor (TLR) signaling plays an important role in the development of the hypoferremic response, but how downstream signaling events affect genes involved in iron metabolism is incompletely understood. We investigated the involvement of MyD88-dependent (MyD88) and MyD88-independent (TRIF) TLR signaling in the development of hypoferremia. Using MyD88-deficient and TRIF-deficient mice, we show that MyD88 and TRIF signaling pathways are critical for up-regulation by lipopolysaccharide (LPS) of the iron regulator hepcidin. In addition, MyD88 signaling is required for the induction of lipocalin 2 secretion and iron sequestration in the spleen. Activation of TLR4 and TLR3 signaling through LPS and polyinosinic:polycytidylic acid [poly(I:C)] treatments resulted in rapid down-regulation of HFE protein [encoded by the hemochromatosis gene (Hfe)] and ferroportin [encoded by solute carrier family 40 (iron-regulated transporter), member 1 (Slc40a1)] expression in the spleen, independent of MyD88 or TRIF signaling and proinflammatory cytokine production. However, lack of MyD88 signaling significantly impaired the hypoferremic response triggered by LPS, indicating that ferroportin and HFE protein down-regulation alone are insufficient to maintain hypoferremia. The extent of the hypoferremic response was found to be limited by initial, basal iron levels. Together, these results suggest that targeting specific TLR signaling pathways by affecting the function of adaptor molecules may provide new strategies to counteract iron sequestration within macrophages during inflammation.
authors.affiliation: Montreal Cancer Institute, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Layoun
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Annie
authors.initials: A
authors.lastname: Calvé
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000502:physiology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology; D007501:Iron / Q000097:blood; D000090463:Iron Deficiencies; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology*; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology; D015854:Up-Regulation; D000098742:Ferroportin
chemical_list: D000209:Acute-Phase Proteins; D033942:Adaptor Proteins, Vesicular Transport; D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D015850:Interleukin-6; D007501:Iron; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D015513:Oncogene Proteins; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D000098742:Ferroportin; C579599:Hamp protein, mouse; C499535:Hfe protein, mouse; C476286:Ticam1 protein, mouse; C071332:Lcn2 protein, mouse