Volume 6 Supplement 3

Global Arthritis Research Network (GARN): 4th World Congress on Arthritis in Montreal

Open Access

The nonsense allele oblivious reveals a sensor of di-acylglycerides acting in conjunction with TLR2 and TLR6

  • K Hoebe1,
  • K Tabeta1,
  • P Georgel1,
  • X Du1,
  • S Mudd1,
  • S Sovath1,
  • L Shamel1,
  • T Hartung2,
  • Ul Zähringer3 and
  • B Beutler1
Arthritis Res Ther20046(Suppl 3):13

DOI: 10.1186/ar1347

Published: 13 September 2004

The mammalian Toll-like receptors (TLRs) activate cells of the innate immune system when stimulated by diverse ligands of microbial origin. In some instances, these ligands are directly engaged by the TLRs; however, this is not necessarily true in all cases. TLR2 recognizes multiple, structurally disparate microbial ligands, consistent with a requirement for co-receptors in ligand binding. Using N-ethyl-N-nitrosourea, we generated the recessive immunodeficiency phenotype oblivious, in which macrophages show diminished awareness of the S-enantiomer of the di-acylated bacterial lipopeptide MALP-2 and lipoteichoic acid, together with spontaneous ocular colonization by Gram-positive organisms and hypersusceptibility to Staphylococcus aureus infection. Oblivious macrophages readily detect the tri-acylated bacterial lipopeptide PAM3CSK4 as well as zymosan, revealing that some TLR2 ligands are activated via an Oblivious-independent pathway. The gene responsible for the oblivious phenotype has been positionally cloned. In its ability to carry the lipoteichoic acid and MALP-2 signal to the transmembrane signaling receptors TLR2 and TLR6, Oblivious serves a function analogous to CD14, which concentrates the lipopolysacchardide signal for transduction by TLR4. Besides microbial molecules, oblivious also serves as a receptor for endogenous molecules and may mediate (some) of the inflammatory events involved in the development of atherosclerosis.

Authors’ Affiliations

(1)
The Scripps Research Institute
(2)
Department of Biochemical Pharmacology, University of Konstanz
(3)
Research Center Borstel, Leipniz-center for Medicine and Bioscience

Copyright

© The Author(s) 2004

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