Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (<i>Tlr4</i>)

TLDR

Bacterial lipopolysaccharide induces a strong proinflammatory response, and genetic studies have linked this response to a mutant Lps allele on mouse chromosome 4 that confers natural endotoxin tolerance in C3H/HeJ and C57BL/10ScCr mice. Mapping of the Lps locus narrowed it to a 1.7‑Mb interval containing three genes, among them Tlr4, a receptor known to mediate LPS signaling. C3H/HeJ mice carry a P712H point mutation in Tlr4, while C57BL/10ScCr mice lack Tlr4 entirely, demonstrating that loss or alteration of Tlr4 function underlies endotoxin tolerance.

Abstract

Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinflammatory state in the infected host. Genetic regulation of this response has been localized to the Lps locus on mouse chromosome 4, through study of the C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr mice are homozygous for a mutant Lps allele (Lpsd/d) that confers hyporesponsiveness to LPS challenge, and therefore exhibit natural tolerance to its lethal effects. Genetic and physical mapping of 1,345 backcross progeny segregating this mutant phenotype confined Lps to a 0.9-cM interval spanning 1.7 Mb. Three transcription units were identified within the candidate interval, including Toll-like receptor 4 (Tlr4), part of a protein family with members that have been implicated in LPS-induced cell signaling. C3H/HeJ mice have a point mutation within the coding region of the Tlr4 gene, resulting in a nonconservative substitution of a highly conserved proline by histidine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4. Identification of distinct mutations involving the same gene at the Lps locus in two different hyporesponsive inbred mouse strains strongly supports the hypothesis that altered Tlr4 function is responsible for endotoxin tolerance.