CD14 is required for MyD88-independent LPS signaling.

Abstract

The recessive mutation 'Heedless' (hdl) was detected in third-generation N-ethyl-N-nitrosourea-mutated mice that showed defective responses to microbial inducers. Macrophages from Heedless homozygotes signaled by the MyD88-dependent pathway in response to rough lipopolysaccharide (LPS) and lipid A, but not in response to smooth LPS. In addition, the Heedless mutation prevented TRAM-TRIF-dependent signaling in response to all LPS chemotypes. Heedless also abolished macrophage responses to vesicular stomatitis virus and substantially inhibited responses to specific ligands for the Toll-like receptor 2 (TLR2)-TLR6 heterodimer. The Heedless phenotype was positionally ascribed to a premature stop codon in Cd14. Our data suggest that the TLR4-MD-2 complex distinguishes LPS chemotypes, but CD14 nullifies this distinction. Thus, the TLR4-MD-2 complex receptor can function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent signaling.

• Authors: Zhengfan Jiang, Philippe Georgel, Xin Du, Louis Shamel, Sosathya Sovath, Suzanne Mudd, Michael Huber, Christoph Kalis, Simone Keck, Chris Galanos, Marina Freudenberg, Bruce Beutler
• Journal: Nature immunology (Nat Immunol) Vol. 6 Issue 6 Pg. 565-70 (Jun 2005) ISSN: 1529-2908 [Print] United States
• PMID: 15895089 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, Differentiation
• Antigens, Ly
• Interferon Type I
• Lipopolysaccharide Receptors
• Lipopolysaccharides
• Ly96 protein, mouse
• Lymphocyte Antigen 96
• Multiprotein Complexes
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, Immunologic
• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Antigens, Differentiation (genetics, metabolism)
• Antigens, Ly (chemistry, metabolism)
• In Vitro Techniques
• Interferon Type I (biosynthesis)
• Lipopolysaccharide Receptors (genetics, metabolism)
• Lipopolysaccharides (toxicity)
• Lymphocyte Antigen 96
• Macrophages, Peritoneal (drug effects, immunology, metabolism)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Mutant Strains
• Multiprotein Complexes
• Mutation
• Myeloid Differentiation Factor 88
• Receptors, Immunologic (chemistry, genetics, metabolism)
• Signal Transduction
• Toll-Like Receptor 4
• Vesicular stomatitis Indiana virus (pathogenicity)