The Tlr4Lps-del spontaneous mutation exhibits a defective response to LPS stimulation and affects Toll signaling pathways involved with inflammation, including susceptibility to various bacterial infections, effects of tissue ischemia (including cerebral and retinal ischemia), myocardial infarction, neurodegeneration, and tumor immune responses.Read More +
The stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces the release of proinflammatory cytokines that activate immune responses. The Tlr4Lps-del spontaneous mutation corresponds to a 74723 bp deletion that completely removes the Tlr4 coding sequence. No mRNA or protein is expressed. Homozygous mutants exhibit a defective response to LPS stimulation. The functionally similar Tlr4Lps-d mutation found in C3H/HeJ mice (#000659) is a point mutation that causes an amino acid substitution.
Tlr4 -deficient mice display significantly reduced expression of proinflammatory genes compared to controls 24 h after reperfusion triggered by retinal ischemic injury. These include transcriptional factor p65 (Rela), tumor necrosis factor (Thf), interleukin 6 (Il6), chemokine (C-C motif) ligand 2 (Ccl2), chemokine (C-C motif) ligand 5 (Ccl5), chemokine (C-X-C motif) ligand 10 (Cxcl10), cytochrome b-245, beta polypeptide (Cybb), nitric oxide synthase 2 (Nos2), and intercellular adhesion molecule 1 (Icam1) (Dvoriantchikova et al., 2010).
The effect of TLR4 on tumor progression appears to depend on which cells TLR4 resides and the particular ligand involved. For example, enhanced prostrate tumor progression as a result of TLR4 response to a tumor-derived ligand such as Peroxiredoxin is not seen in the Tlr4 deficient mutant mice (Riddell et al., 2011). Conversely, tumor inhibition seen in wild type mice when B16 melanoma cells were stimulated in vitro with LPS was not seen in mutant mice (Nunez et al., 2012).
TLR4 signaling may also act as innate neuroprotective mechanism through clearance of alpha-synuclein as TLR4 ablation impairs the phagocytic response of microglia to alpha-synuclein and enhances neurodegeneration (Stefanova et al. 2011).
Abnormal response to lipopolysaccharide was observed in the inbred strain C57BL/10ScN in the 1970s. The phenotype was subsequently identified as a mutation in the Tlr4 gene. This strain originated from the C57BL/10ScN colony at NCI Frederick and was transferred to the laboratory of Dr. James Thomas, University of Texas Southwestern Medical Center. The allele was introgressed into C57BL/6 by backcrossing for at least five generations. The strain was donated to The Jackson Laboratory Repository in 2008.
|Allele Name||defective lipopolysaccharide response, deletion|
|Allele Synonym(s)||TLR4-KO; TLR4lps-; Tlr4-|
|Gene Symbol and Name||Tlr4, toll-like receptor 4|
|Gene Synonym(s)||ARMD10; CD284; Lps; Lps; RAS-like, family 2, locus 8; Rasl2-8; Rasl2-8; TLR-4; TOLL; lipopolysaccharide response; lipopolysaccharide response|
|Strain of Origin||C57BL/10ScN|
|General Note||C57BL/10ScN, C57BL/10ScNJ, and C57BL10/ScCr mice carry this allele.|
|Molecular Note||This allele has been characterized by lack of mRNA owing to a deletion of the locus. 74723bp of genomic DNA sequence have been removed, apparently encompasing only the Tlr4 gene.|
When maintaining a live colony, these mice are bred as homozygotes.
|Please inquire about possible genotypes.|
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