Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More Efficiently Than Antagonizing the Toll-like Receptor 4–MD2 Complex

• Published in: The Journal of infectious diseases Vol. 214; no. 1; pp. 140 - 150
• Main Authors: Gustavsen, Alice, Nymo, Stig, Landsem, Anne, Christiansen, Dorte, Ryan, Liv, Husebye, Harald, Lau, Corinna, Pischke, Søren E., Lambris, John D., Espevik, Terje, Mollnes, Tom E.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-07-2016
• Subjects: Anti-Bacterial Agents - therapeutic use; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; Basic medical, dental and veterinary science disciplines: 710; Cytokines - blood; Escherichia; Escherichia coli - drug effects; Humans; Inflammation - blood; Inflammation - drug therapy; Inflammation - etiology; Inflammation - microbiology; Lipopolysaccharide Receptors - blood; Lipopolysaccharide Receptors - drug effects; Major and Brief Reports; Medical disciplines: 700; Medical immunology: 716; Medisinsk immunologi: 716; Medisinske Fag: 700; PATHOGENESIS AND HOST RESPONSE; Sepsis - drug therapy; Sepsis - microbiology; Staphylococcal Infections - complications; Staphylococcal Infections - drug therapy; Staphylococcus; Staphylococcus aureus - drug effects; Toll-Like Receptor 4 - drug effects; VDP; eritoran; treatment; CD14; TLR; complement; sepsis
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiw100

Background. Single inhibition of the Toll-like receptor 4 (TLR4)–MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood. Methods. Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry. Results. Lipopolysaccharide (LPS)–induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS-binding to HEK-293E cells transfected with CD14 and Escherichia coli–induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti-CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli–induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria-induced inflammatory responses (mean P < .0001). Conclusions. Whole bacteria–induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis.