Essential role of MD-2 in LPS responsiveness and TLR4 distribution

• Published in: Nature immunology Vol. 3; no. 7; pp. 667 - 672
• Main Authors: Miyake, Kensuke, Nagai, Yoshinori, Akashi, Sachiko, Nagafuku, Masakazu, Ogata, Masato, Iwakura, Yoichiro, Akira, Shizuo, Kitamura, Toshio, Kosugi, Atsushi, Kimoto, Masao
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-07-2002
• Subjects: Animals; Antigens, Surface - genetics; Antigens, Surface - immunology; B-Lymphocytes - drug effects; Cells, Cultured; Dendritic Cells - drug effects; Dendritic Cells - immunology; Disease Models, Animal; Drosophila Proteins; Female; Interleukin-12 - biosynthesis; Interleukin-6 - biosynthesis; Intracellular Fluid - immunology; Lipid A - immunology; Lipid A - pharmacology; Lipopolysaccharide Receptors - immunology; Lymphocyte Antigen 96; Macrophages - drug effects; Macrophages - immunology; Male; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cell Surface - immunology; Salmonella Infections - immunology; Salmonella typhimurium; Salmonella typhimurium - immunology; Shock, Septic - immunology; Spleen - cytology; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni809

Toll-like receptor 4 (TLR4) mediates lipopolysaccharide (LPS) signaling in a variety of cell types. MD-2 is associated with the extracellular domain of TLR4 and augments TLR4-dependent LPS responses in vitro. We show here that MD-2(-/-) mice do not respond to LPS, do survive endotoxic shock but are susceptible to Salmonella typhimurium infection. We found that in MD-2(-/-) embryonic fibroblasts, TLR4 was not able to reach the plasma membrane and predominantly resided in the Golgi apparatus, whereas TLR4 was distributed at the leading edge surface of cells in wild-type embryonic fibroblasts. Thus, MD-2 is essential for correct intracellular distribution and LPS-recognition of TLR4.