Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2

Adaptive immunity generally refers to the ability of lymphocytes to recognize microbial, viral and fungal proteins via T cell receptors and antibodies. More ancestral and widespread innate immune mechanisms include those responsible for recognition of microbial glycolipids. Lipopolysaccharide (LPS) is the best studied, and arguably one of the most important of bacterial products because of its role in innate immune responses and endotoxin-mediated sepsis. Converging studies in two independent fields have recently led to the identification of LPS recognition molecules utilized by mammalian cells. Toll-like receptor 4 (TLR4) was identified as a mammalian homologue of the Toll receptor, which recognized fungi in the Drosophila's immune system. Spontaneous and targeted mutations identified TLR4 as an LPS recognition molecule. Separate studies of a Radioprotective 105 (RP105) and MD-1 heterodimer expressed by cells led to the identification of MD-2 as a molecule associated with TLR4. Very recent in vivo studies have now revealed an essential contribution of MD-2 to LPS recognition. These findings further our understanding of protective, as well as detrimental innate immune mechanisms and may lead to new therapies for endotoxin shock.