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

Details

Serval ID
serval:BIB_7916D743A3A0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Roger T., Froidevaux C., Le Roy D., Reymond M.K., Chanson A.L., Mauri D., Burns K., Riederer B.M., Akira S., Calandra T.
ISSN
1091-6490
Publication state
Published
Issued date
02/2009
Peer-reviewed
Oui
Volume
106
Number
7
Pages
2348-2352
Language
english
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.
Keywords
endotoxic shock, Gram-negative bacteria, lipopolysaccharide, TLR4
Pubmed
Web of science
Open Access
Yes
Create date
12/02/2009 15:46
Last modification date
20/08/2019 15:35
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