title: Liquid-crystalline ordering of antimicrobial peptide-DNA complexes controls TLR9 activation.
abstract: Double-stranded DNA (dsDNA) can trigger the production of type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by binding to endosomal Toll-like receptor-9 (TLR9; refs 1-5). It is also known that the formation of DNA-antimicrobial peptide complexes can lead to autoimmune diseases via amplification of pDC activation. Here, by combining X-ray scattering, computer simulations, microscopy and measurements of pDC IFN production, we demonstrate that a broad range of antimicrobial peptides and other cationic molecules cause similar effects, and elucidate the criteria for amplification. TLR9 activation depends on both the inter-DNA spacing and the multiplicity of parallel DNA ligands in the self-assembled liquid-crystalline complex. Complexes with a grill-like arrangement of DNA at the optimum spacing can interlock with multiple TLR9 like a zipper, leading to multivalent electrostatic interactions that drastically amplify binding and thereby the immune response. Our results suggest that TLR9 activation and thus TLR9-mediated immune responses can be modulated deterministically.
authors.affiliation: Bioengineering Department, Chemistry &Biochemistry Department, California Nano Systems Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.affiliation: 1] Bioengineering Department, Chemistry &Biochemistry Department, California Nano Systems Institute, University of California, Los Angeles, California 90095, USA [2] Hefei National Laboratory for Physical Sciences at Microscale, Department of Polymer Science and Engineering, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jin
authors.affiliation: 1] Department of Dermatology, Lausanne University Hospital CHUV, 1009 Lausanne, Switzerland [2] Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lande
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK.
authors.forename: Tine
authors.initials: T
authors.lastname: Curk
authors.affiliation: Bioengineering Department, Chemistry &Biochemistry Department, California Nano Systems Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Wujing
authors.initials: W
authors.lastname: Xian
authors.affiliation: Bioengineering Department, Chemistry &Biochemistry Department, California Nano Systems Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Lee
authors.affiliation: 1] Department of Dermatology, Lausanne University Hospital CHUV, 1009 Lausanne, Switzerland [2] Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Frasca
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK.
authors.forename: Daan
authors.initials: D
authors.lastname: Frenkel
authors.affiliation: 1] Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK [2] Department for Theoretical Physics, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia [3] International Center for Soft Matter Research, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Jure
authors.initials: J
authors.lastname: Dobnikar
authors.affiliation: Department of Dermatology, Lausanne University Hospital CHUV, 1009 Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.affiliation: Bioengineering Department, Chemistry &Biochemistry Department, California Nano Systems Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Gerard C L
authors.initials: GC
authors.lastname: Wong
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D003198:Computer Simulation; D018899:CpG Islands; D003460:Crystallization; D004247:DNA / Q000737:chemistry*; D003713:Dendritic Cells / Q000166:cytology; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D050866:Liquid Crystals; D009010:Monte Carlo Method; D009841:Oligonucleotides / Q000737:chemistry; D012542:Scattering, Radiation; D055672:Static Electricity; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014965:X-Rays; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D007370:Interferon Type I; D016898:Interferon-alpha; D009841:Oligonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA; D054804:Cathelicidins