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


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.

SUBMITTER: Roger T 

PROVIDER: S-EPMC2650125 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Roger Thierry T   Froidevaux Céline C   Le Roy Didier D   Reymond Marlies Knaup MK   Chanson Anne-Laure AL   Mauri Davide D   Burns Kim K   Riederer Beat Michel BM   Akira Shizuo S   Calandra Thierry T  

Proceedings of the National Academy of Sciences of the United States of America 20090130 7


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 primar  ...[more]

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