Receptor for advanced glycation end-products (RAGE) detects nucleic acids and promotes DNA uptake into endosomes, which in turn lowers the immune recognition threshold for TLR9 activation.

No abstract

Background: Genetic variation of SNP rs11536889 in 3Ј-UTR of TLR4 is implicated in certain diseases, including periodontitis, gastric atrophy, and prostate cancer. Results: The G allele of rs11536889 inhibited translation, but not transcription, of TLR4. Conclusion: Genetic variation of rs11536889 regulates TLR4 expression. Significance: Polymorphism in rs11536889 could be an excellent genetic marker for the diseases caused by TLR4-ligands.

Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE-DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.

These results suggest that GTC suppresses LPS-induced bone resorption by inhibiting IL-1beta production or by directly inhibiting osteoclastogenesis.