The sole gateway to endotoxin response: How LPS was identified as Tlr4, and its role in innate immunity

Tlr4 has emerged as a specific conduit for the bacterial lipopolysaccharide (LPS) response. The fact that such a protein exists, and furthermore, the fact that it is one member of a family of proteins expressed by mononuclear cells, yields considerable insight into the mechanism by which phagocytes "see" the microbial universe. It cannot yet be assumed that all the Tlrs have specificity comparable to that of Tlr4, but it is probable that they do, given the molecular constraints to which all proteins are subject. Indeed, it is remarkable that Tlr4 is able to sense so diverse an array of LPS molecules as it does. The total number of Tlr proteins is not yet known. Although approximately 30 leucine-rich proteins bearing Toll-like cytoplasmic domains might be anticipated based on a survey of the genes in Drosophila, far fewer Toll-like genes have been found in mammals to date, although approximately 2 million expressed sequence tag sequences are now archived, and much of the genome has been covered. Some of the Toll-like proteins are, in fact, cytokine receptors. Ten leucine-rich Tlrs have been reported so far. Even a small number of receptors might be sufficient to confer recognition of most pathogens, be they fungi, bacteria, or protozoa. Some such receptors may also play developmental roles. The mutational deletion of Tlr genes alone and in combination with one another may help to establish the functions of each member of this newly emergent family of proteins.