title: Synergistic inflammation is induced by blood degradation products with microbial Toll-like receptor agonists and is blocked by hemopexin.
abstract: Detection of microbial components by immune cells via Toll-like receptors (TLRs) with subsequent induction of inflammation is essential for host defense. However, an overactive immune response can cause tissue damage and sepsis. The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein. These studies suggest that hemoglobin and heme may substantially contribute to microbe-induced inflammation when bacterial or viral infection coexists with blood degradation and that hemopexin may play a role in controlling inflammation in such settings.
authors.affiliation: Infectious Disease Unit, Massachusetts General Hospital, Boston, MA 02129, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Lin
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kwak
authors.forename: Fatima
authors.initials: F
authors.lastname: Sammy
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Sujatha
authors.initials: S
authors.lastname: Thundivalappil
authors.forename: Guangjie
authors.initials: G
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.forename: H Shaw
authors.initials: HS
authors.lastname: Warren
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000276:immunology; D001769:Blood / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology; D006418:Heme / Q000276:immunology*; D006454:Hemoglobins / Q000276:immunology*; D006466:Hemopexin / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D013211:Staphylococcus aureus / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D001427:Bacterial Toxins; D016207:Cytokines; D006454:Hemoglobins; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D006418:Heme; D006466:Hemopexin