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CD14 is required for MyD88-independent LPS signaling

Nature Immunology volume 6, pages 565–570 (2005)Cite this article

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.

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Figure 1: Rough LPS and TLR2-6 specificity of the Heedless mutation.
Figure 2: Heedless prevents IFN-β induction by LPS.
Figure 3: Macrophages of Heedless mice are hypersensitive to cytolysis induced by VSV.
Figure 4: Detection of Heedless, a mutation in Cd14, by restriction endonuclease cleavage.
Figure 5: Rescue of smooth LPS responsiveness in Cd14 homozygous mutant cells by recombinant mouse CD14.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (AI050241), the Landesstiftung (P-LS-AL/3) and the Deutsche Forschungsgemeinschaft (FR 448/4-2).

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Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Zhengfan Jiang, Philippe Georgel, Xin Du, Louis Shamel, Sosathya Sovath, Suzanne Mudd & Bruce Beutler

  2. Department of Molecular Immunology, Institute for Biology III, Albert-Ludwigs University Freiburg, Freiburg, 79108, Germany

    Michael Huber & Christoph Kalis

  3. Max-Planck Institute for Immunobiology, Freiburg, 79108, Germany

    Simone Keck, Chris Galanos & Marina Freudenberg

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Correspondence to Bruce Beutler.

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Supplementary information

Supplementary Fig. 1

The Heedless mutation, mapped and identified by sequencing. (PDF 153 kb)

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Jiang, Z., Georgel, P., Du, X. et al. CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6, 565–570 (2005). https://doi.org/10.1038/ni1207

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