TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide.

Proceedings of the National Academy of Sciences of the United States of America 2013 Mar 19

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Although endogenous ligands for Toll-like receptor (TLR)4-myeloid differentiation factor 2 (MD2) have not been well-understood, we here report that a globo-series glycosphingolipid, globotetraosylceramide (Gb4), attenuates the toxicity of lipopolysaccharides (LPSs) by binding to TLR4-MD-2. Because α1,4-galactosyltransferase (A4galt)-deficient mice lacking globo-series glycosphingolipids showed higher sensitivity to LPS than wild-type mice, we examined mechanisms by which globo-series glycosphingolipids attenuate LPS toxicity. Cultured endothelial cells lacking A4galt showed higher expression of LPS-inducible genes upon LPS treatment. In turn, introduction of A4galt cDNA resulted in the neo expression of Gb4, leading to the reduced expression of LPS-inducible genes. Exogenous Gb4 induced similar effects. As a mechanism for the suppressive effects of Gb4 on LPS signals, specific binding of Gb4 to the LPS receptor TLR4-MD-2 was demonstrated by coprecipitation of Gb4 with recombinant MD-2 and by native PAGE. A docking model also supported these data. Taken together with colocalization of TLR4-MD-2 with Gb4 in lipid rafts after LPS stimulation, it was suggested that Gb4 competes with LPS for binding to TLR4-MD-2. Finally, administration of Gb4 significantly protected mice from LPS-elicited mortality. These results suggest that Gb4 is an endogenous ligand for TLR4-MD-2 and is capable of attenuating LPS toxicity, indicating the possibility for its therapeutic application in endotoxin shock.

Citation

Yuji Kondo, Kazutaka Ikeda, Noriyo Tokuda, Chiaki Nishitani, Umeharu Ohto, Sachiko Akashi-Takamura, Yasutomo Ito, Makoto Uchikawa, Yoshio Kuroki, Ryo Taguchi, Kensuke Miyake, Qing Zhang, Keiko Furukawa, Koichi Furukawa. TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide. Proceedings of the National Academy of Sciences of the United States of America. 2013 Mar 19;110(12):4714-9