Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 7; pp. 2348 - 2352
• Main Authors: Roger, Thierry, Froidevaux, Céline, Le Roy, Didier, Reymond, Marlies Knaup, Chanson, Anne-Laure, Mauri, Davide, Burns, Kim, Riederer, Beat Michel, Akira, Shizuo, Calandra, Thierry
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.02.2009; National Acad Sciences
• Subjects: Amino acids; Animals; Antibodies; Biological Sciences; Cytokines; Data processing; Differentiation; E coli; Endotoxemia; Endotoxins; Escherichia; Escherichia coli; Escherichia coli - metabolism; Fusion protein; Gene Expression Regulation, Bacterial; Gram-negative bacteria; Gram-Negative Bacteria - metabolism; Humans; Immunoglobulin G; Immunoglobulin G - chemistry; Intracellular signalling; Lipopolysaccharides; Lipopolysaccharides - metabolism; Macrophages; Mice; Mice, Inbred C57BL; Models, Genetic; Myeloid Differentiation Factor 88 - genetics; Proteins; Recombinant Fusion Proteins - metabolism; Rodents; Sepsis; Sepsis - genetics; Sepsis - microbiology; Sepsis - pathology; Septic shock; Shock; Signal transduction; T cell receptors; Time Factors; TLR4 protein; Toll like receptors; Toll-Like Receptor 4 - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0808146106

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from Gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of Gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in Gram-negative sepsis, we first showed that TLR4⁻/⁻ and myeloid differentiation primary response gene 88 (MyD88)⁻/⁻ mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2⁻/⁻ and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for Gram-negative sepsis.