TLR SIGNALING dsRNA Delivery Service

CD14 is a glycosylphosphatidylinositol (GPI)-anchored pattern recognition receptor that is involved in activation of Toll-like receptors (TLRs) at the cell surface (see Finberg and Kurt-Jones). For example, it binds to lipopolysaccharide (LPS) and viruses to present these foreign agents to TLR4 and TLR2, respectively. Lee et al. now report that CD14 is also involved in presentation of double-stranded RNA (dsRNA) to the endosomal-localized TLR3 and that CD14 amplifies the cellular response to dsRNA. Lee et al. noted that bone marrow-derived macrophages (BMDMs) from CD14-deficient mice showed lower activation of nuclear factor B (NF-B) and interleukin production in response to the dsRNA mimic polyinosine-polycytidylic acid (pIpC) than did wild-type BMDMs. In human embryonic kidney 293 (HEK293) cells transfected with TLR3 and CD14 along with TLR3 reporter genes, the response to pIpC was enhanced in a dose-dependent manner by CD14. Transfected Chinese hamster ovary (CHO) cells expressing CD14 with and without TLR3 showed internalization of pIpC when short fragments of pIpC (pIpCsf) were applied to the cells. Ligand-binding assays showed that the CD14 directly bound pIpCsf and that this binding was inhibited by related RNAs but not by the DNA derivative pdIpdC. Confocal microscopy showed that CD14 and TLR3 colocalized in the absence of pIpC in endosomes and, upon internalization of pIpCsf, all three were localized in lysosomes. Thus, CD14 appears to deliver dsRNA to TLR3. Whether the interaction of CD14 with lipid rafts or signaling components--such as Src and G proteins, which are believed to be important for the interaction between CD14 and cell surface TLRs--is involved in the amplification of the TLR3 signal remains to be determined.

R. W. Finberg, E. A. Kurt-Jones, CD14: Chaperone or matchmaker? Immunity 24, 127-129 (2006). [PubMed]

H.-K. Lee, S. Dunzendorfer, K. Soldau, P. S. Tobias, Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity 24, 153-163 (2006). [PubMed]

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