Synergistic inflammation is induced by blood degradation products with microbial Toll-like receptor agonists and is blocked by hemopexin.
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.
Lin
Tian
T
Infectious Disease Unit, Massachusetts General Hospital, Boston, MA 02129, USA.
Kwak
Young Ho
YH
Sammy
Fatima
F
He
Ping
P
Thundivalappil
Sujatha
S
Sun
Guangjie
G
Chao
Wei
W
Warren
H Shaw
HS
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
D001427:Bacterial Toxins; D016207:Cytokines; D006454:Hemoglobins; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D006418:Heme; D006466:Hemopexin