title: TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells.
abstract: Toll-like receptors (TLRs) mediate host responses to bacterial gene products. As the airway epithelium is potentially exposed to many diverse inhaled bacteria, TLRs involved in defense of the airways must be broadly responsive, available at the exposed apical surface of the cells, and highly regulated to prevent activation following trivial encounters with bacteria. We demonstrate that TLR2 is enriched in caveolin-1-associated lipid raft microdomains presented on the apical surface of airway epithelial cells after bacterial infection. These receptor complexes include myeloid differentiation protein (MyD88), interleukin-1 receptor-activated kinase-1, and TNF receptor-associated factor 6. The signaling capabilities of TLR2 are amplified through its association with the asialoganglioside gangliotetraosylceramide (Gal beta 1,2GalNAc beta 1,4Gal beta 1,4Glc beta 1,1Cer), which has receptor function itself for many pulmonary pathogens. Ligation of either TLR2 or asialoGM1 by ligands with specificity for either receptor, by Pseudomonas aeruginosa, or by Staphylococcus aureus stimulates IL-8 production through activation of NF-kappa B, as mediated by TLR2 and MyD88. Thus, TLR2 in association with asialo-glycolipids presented within the context of lipid rafts provides a broadly responsive signaling complex at the apical surfaces of airway cells to initiate the host response to potential bacterial infection.
authors.affiliation: Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Soong
authors.forename: Bharat
authors.initials: B
authors.lastname: Reddy
authors.forename: Sach
authors.initials: S
authors.lastname: Sokol
authors.forename: Robert
authors.initials: R
authors.lastname: Adamo
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000378:metabolism; D002240:Carbohydrate Sequence; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology; D005732:Gangliosides; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D021962:Membrane Microdomains / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000472:pathogenicity; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C011258:G(A1) ganglioside; D005732:Gangliosides; D006028:Glycosphingolipids; D016209:Interleukin-8; D008024:Ligands; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors