title: CD14 is a coreceptor of Toll-like receptors 7 and 9.
abstract: Recognition of pathogens by the innate immune system requires proteins that detect conserved molecular patterns. Nucleic acids are recognized by cytoplasmic sensors as well as by endosomal Toll-like receptors (TLRs). It has become evident that TLRs require additional proteins to be activated by their respective ligands. In this study, we show that CD14 (cluster of differentiation 14) constitutively interacts with the MyD88-dependent TLR7 and TLR9. CD14 was necessary for TLR7- and TLR9-dependent induction of proinflammatory cytokines in vitro and for TLR9-dependent innate immune responses in mice. CD14 associated with TLR9 stimulatory DNA in precipitation experiments and confocal imaging. The absence of CD14 led to reduced nucleic acid uptake in macrophages. Additionally, CD14 played a role in the stimulation of TLRs by viruses. Using various types of vesicular stomatitis virus, we showed that CD14 is dispensable for viral uptake but is required for the triggering of TLR-dependent cytokine responses. These data show that CD14 has a dual role in nucleic acid-mediated TLR activation: it promotes the selective uptake of nucleic acids, and it acts as a coreceptor for endosomal TLR activation.
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Christoph L
authors.initials: CL
authors.lastname: Baumann
authors.forename: Irene M
authors.initials: IM
authors.lastname: Aspalter
authors.forename: Omar
authors.initials: O
authors.lastname: Sharif
authors.forename: Andreas
authors.initials: A
authors.lastname: Pichlmair
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Manuela
authors.initials: M
authors.lastname: Bruckner
authors.forename: Pawel
authors.initials: P
authors.lastname: Pasierbek
authors.forename: Karin
authors.initials: K
authors.lastname: Aumayr
authors.forename: Melanie
authors.initials: M
authors.lastname: Planyavsky
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D000077271:Imiquimod; D009980:Influenza A virus / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000032:analysis / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D040901:Proteomics; D051199:Toll-Like Receptor 7 / Q000032:analysis / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000032:analysis / Q000502:physiology*
chemical_list: D000634:Aminoquinolines; C408982:CPG-oligonucleotide; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D000077271:Imiquimod