The Lps locus: genetic regulation of host responses to bacterial lipopolysaccharide

Lipopolysaccharide (LPS), an abundant glycolipid of the outer membrane of gram-negative bacteria, is able to provoke a generalized proinflammatory response in the infected host. Genetic regulation of this trait has been localized to the Lps locus on mouse chromosome 4. Several inbred mouse strains, including C3H/HeJ, C57BL/10ScNCr and C57BL/10ScCr, bear mutations at the Lps locus (Lps(d)) that confer hyporesponsiveness to the immunostimulatory properties of LPS and susceptibility to overwhelming gram-negative bacterial infection. The phenotypic expression of Lps(d) is pleiotropic, affecting several cell types crucial to host defense, including the macrophage. By positional cloning, Toll-like receptor 4 (Tlr4), a transmembrane protein with a cytoplasmic domain that bears homology to the Interleukin-1 receptor, has been identified as the gene encoded by Lps. Tlr4 is a member of a novel gene family that participates in host defense against microbial infection in plants, invertebrates and mammals. Discovery of the molecular basis of the Lps mutation represents a significant advance in defining the fundamental mechanisms of cellular activation by LPS.