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

Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2348-52. doi: 10.1073/pnas.0808146106. Epub 2009 Jan 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Escherichia coli / metabolism
  • Gene Expression Regulation, Bacterial*
  • Gram-Negative Bacteria / metabolism*
  • Humans
  • Immunoglobulin G / chemistry
  • Lipopolysaccharides / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Myeloid Differentiation Factor 88 / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sepsis / genetics
  • Sepsis / microbiology*
  • Sepsis / pathology
  • Time Factors
  • Toll-Like Receptor 4 / physiology*

Substances

  • Immunoglobulin G
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Recombinant Fusion Proteins
  • Toll-Like Receptor 4