CD14 is required for MyD88-independent LPS signaling

Zhengfan Jiang, Philippe Georgel, Xin Du, Louis Shamel, Sosathya Sovath, Suzanne Mudd, Michael Huber, Christoph Kalis, Simone Keck, Chris Galanos, Marina Freudenberg, Bruce Beutler

Research output: Contribution to journalArticle

478 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)565-570
Number of pages6
JournalNature Immunology
Issue number6
StatePublished - Dec 8 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Jiang, Z., Georgel, P., Du, X., Shamel, L., Sovath, S., Mudd, S., Huber, M., Kalis, C., Keck, S., Galanos, C., Freudenberg, M., & Beutler, B. (2005). CD14 is required for MyD88-independent LPS signaling. Nature Immunology, 6(6), 565-570.