Summary

The human innate immune system identifies Gram-negative bacteria by recognizing lipopolysaccharides (LPS), components of the microbial cell wall (1). This detection triggers massive inflammatory responses that help eradicate infections, but may also result in immunopathology if regulated improperly. Hence, LPS is also referred to as endotoxin. More than a century after its discovery, the molecular basis for the inflammatory activity of endotoxin was finally revealed by the discovery that Toll-like receptor 4 (TLR4) induces innate and adaptive immune responses to LPS (2). TLR4 is the founding member of the mammalian Toll-like receptor family, and its discovery heralded a new age in the study of host-microbe interactions. On pages 1250 and 1246 of this issue, Hagar et al. (3) and Kayagaki et al. (4), respectively, reveal the existence of cellular responses to LPS that do not depend on TLR4. The search for the new LPS receptor can now begin.