MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4

TLDR

Toll‑like receptor 4 (TLR4) is a leucine‑rich repeat protein that mediates innate immune responses and has been implicated as a potential receptor for lipopolysaccharide, although certain mouse strains with TLR4 mutations show reduced LPS responsiveness. The study reports that MD‑2 is required for TLR4‑mediated LPS signaling. MD‑2 associates with TLR4 on the cell surface and confers LPS responsiveness, establishing a receptor complex that links TLR4 to LPS signaling and may inform host defense and disease mechanisms.

Abstract

Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila Toll, a leucine-rich repeat molecule that can trigger innate responses against pathogens. The TLR4 gene has recently been shown to be mutated in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS. However, transfection of TLR4 does not confer LPS responsiveness on a recipient cell line, suggesting a requirement for an additional molecule. Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. MD-2 is thus a link between TLR4 and LPS signaling. Identification of this new receptor complex has potential implications for understanding host defense, as well as pathophysiologic, mechanisms.