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RNA Recognition via TLR7 and TLR8

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Part of the Handbook of Experimental Pharmacology book series (HEP, volume 183)

In this chapter we focus on immunorecognition of RNA by two members of the family of Toll-like receptors (TLRs), TLR7, and TLR8. While any long single-stranded RNA is readily recognized by both TLR7 and TLR8, sequencedependent activation of TLR7 and TLR8 becomes more evident when using short RNA oligonucleotides. RNA oligonucleotides containing sequence motifs for TLR7 and TLR8 are termed is RNA (immunostimulatory RNA). Moreover, short doublestranded RNA oligonucleotides as used for siRNA (short interfering RNA) containing such sequences function primarily as ligands for TLR7 but not TLR8. Even in the presence of appropriate sequence motifs, RNA is not detected by TLR7 and TLR8 when certain chemical modifications are present. Both immunological recognition and ignorance are relevant for the development of RNA-based therapeutics, depending on the clinical setting for which they are developed.

Keywords

Gene Silence Plasmacytoid Dendritic Cell Immunostimulatory Activity siRNA Molecule Innate Antiviral Response 
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References

  1. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783-801CrossRefPubMedGoogle Scholar
  2. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732-738CrossRefPubMedGoogle Scholar
  3. Almofti MR, Harashima H, Shinohara Y, Almofti A, Baba Y, Kiwada H (2003) Cationic liposomemediated gene delivery: Biophysical study and mechanism of internalization. Arch Biochem Biophys 410: 246-253CrossRefPubMedGoogle Scholar
  4. Amarzguioui M, Holen T, Babaie E, Prydz H (2003) Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res 31: 589-595CrossRefPubMedGoogle Scholar
  5. Baltimore D, Becker Y, Darnell JE (1964) Virus-Specific Double-Stranded Rna in PoliovirusInfected Cells. Science 143: 1034-1036CrossRefPubMedGoogle Scholar
  6. Barton GM, Kagan JC, Medzhitov R (2006) Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 7: 49-56CrossRefPubMedGoogle Scholar
  7. Beigelman L, McSwiggen JA, Draper KG, Gonzalez C, Jensen K, Karpeisky AM, Modak AS, Matulic-Adamic J, DiRenzo AB, Haeberli P, et al. (1995) Chemical modification of hammerhead ribozymes. Catalytic activity and nuclease resistance. J Biol Chem 270: 25702-25708CrossRefPubMedGoogle Scholar
  8. Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh DG, Larsson M, Gorelick RJ, Lifson JD, Bhardwaj N (2005) Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 115: 3265-3275CrossRefPubMedGoogle Scholar
  9. Bekeredjian-Ding I, Roth SI, Gilles S, Giese T, Ablasser A, Hornung V, Endres S, Hartmann G (2006) T cell-independent, TLR-induced IL-12p70 production in primary human monocytes. J Immunol 176: 7438-7346PubMedGoogle Scholar
  10. Bekeredjian-Ding IB, Wagner M, Hornung V, Giese T, Schnurr M, Endres S, Hartmann G (2005) Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol 174: 4043-4050PubMedGoogle Scholar
  11. Braasch DA, Jensen S, Liu Y, Kaur K, Arar K, White MA, Corey DR (2003) RNA interference in mammalian cells by chemically-modified RNA. Biochem 42: 7967-7975CrossRefGoogle Scholar
  12. Capodici J, Kariko K, Weissman D (2002) Inhibition of HIV-1 infection by small interfering RNAmediated RNA interference. J Immunol 169: 5196-5201PubMedGoogle Scholar
  13. Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H, Delneste Y (2005) Direct stimulation of human T cells via TLR5 and TLR7/8: Flagellin and R-848 up-regulate proliferation and IFNgamma production by memory CD4 + T cells. J Immunol 175: 1551-1557PubMedGoogle Scholar
  14. Cavaille J, Bachellerie JP (1998) SnoRNA-guided ribose methylation of rRNA: Structural features of the guide RNA duplex influencing the extent of the reaction. Nucleic Acids Res 26: 1576-1587CrossRefPubMedGoogle Scholar
  15. Cekaite L, Furset G, Hovig E, Sioud M (2007) Gene expression analysis in blood cells in response to unmodified and 2′ -modified siRNAs reveals TLR-dependent and independent effects. J Mol Bio 365: 90-108CrossRefGoogle Scholar
  16. Chiu YL, Rana TM (2003) siRNA function in RNAi: A chemical modification analysis. Rna 9: 1034-1048CrossRefPubMedGoogle Scholar
  17. Choe J, Kelker MS, Wilson IA (2005) Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science 309: 581-585CrossRefPubMedGoogle Scholar
  18. Czauderna F, Fechtner M, Dames S, Aygun H, Klippel A, Pronk GJ, Giese K, Kaufmann J (2003) Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucleic Acids Res 31: 2705-2716CrossRefPubMedGoogle Scholar
  19. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529-1531CrossRefPubMedGoogle Scholar
  20. Diebold SS, Massacrier C, Akira S, Paturel C, Morel Y, Reis ESC (2006) Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J of Immun 36: 3256-3267CrossRefGoogle Scholar
  21. Dorsett Y, Tuschl T (2004) siRNAs: applications in functional genomics and potential as therapeutics. Nat Rev Drug Discov 3: 318-329CrossRefPubMedGoogle Scholar
  22. Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T (2001) Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J 20: 6877-6888CrossRefPubMedGoogle Scholar
  23. Field AK, Tytell AA, Lampson GP, Hilleman MR (1967) Inducers of interferon and host resistance. II. Multistranded synthetic polynucleotide complexes. Proc Natl Acad Sci USA 58: 1004-1010CrossRefPubMedGoogle Scholar
  24. Funami K, Matsumoto M, Oshiumi H, Akazawa T, Yamamoto A, Seya T (2004) The cytoplasmic ‘linker region’ in Toll-like receptor 3 controls receptor localization and signaling. Int Immunol 16: 1143-154CrossRefPubMedGoogle Scholar
  25. Gelman AE, Zhang J, Choi Y, Turka LA (2004) Toll-like receptor ligands directly promote activated CD4 + T cell survival. J Immunol 172: 6065-6073PubMedGoogle Scholar
  26. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna M (2006) Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Nat Acad Sci USA 103: 8459-8464CrossRefPubMedGoogle Scholar
  27. Gorden KK, Qiu X, Battiste JJ, Wightman PP, Vasilakos JP, Alkan SS (2006a) Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. J Immunol 177: 8164-8170Google Scholar
  28. Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS (2006b) Cutting edge: Activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 177: 6584-6587Google Scholar
  29. Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Hacker G, Mann M, Karin M (2006) Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439: 204-207CrossRefPubMedGoogle Scholar
  30. Hartmann G, Krieg AM (2000) Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol 164: 944-953PubMedGoogle Scholar
  31. Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, Rasmussen WL, Waldschmidt M, Sajuthi D, Purcell RH, Davis HL, Krieg AM (2000) Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164: 1617-1624PubMedGoogle Scholar
  32. Heidel JD, Hu S, Liu XF, Triche TJ, Davis ME (2004) Lack of interferon response in animals to naked siRNAs. Nat Biotechnol 22: 1579-1582CrossRefPubMedGoogle Scholar
  33. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S (2003) The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8, and 9 subfamily. Eur J Immunol 33: 2987-2997CrossRefPubMedGoogle Scholar
  34. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303: 1526-1529CrossRefPubMedGoogle Scholar
  35. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408: 740-745CrossRefPubMedGoogle Scholar
  36. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, Endres S, Hartmann G (2005) Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 11: 263-270CrossRefPubMedGoogle Scholar
  37. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G (2002) Quantitative expression of Toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168: 4531-4537PubMedGoogle Scholar
  38. Hoshino K, Sugiyama T, Matsumoto M, Tanaka T, Saito M, Hemmi H, Ohara O, Akira S, Kaisho T (2006) IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440: 949-953CrossRefPubMedGoogle Scholar
  39. Jackson AL, Burchard J, Leake D, Reynolds A, Schelter J, Guo J, Johnson JM, Lim L, Karpilow J, Nichols K, Marshall W, Khvorova A, Linsley PS (2006) Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. Rna 12: 1197-1205CrossRefPubMedGoogle Scholar
  40. Judge AD, Bola G, Lee AC, MacLachlan I (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 13: 494-505CrossRefPubMedGoogle Scholar
  41. Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I (2005) Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 23: 457-462CrossRefPubMedGoogle Scholar
  42. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3: 499CrossRefPubMedGoogle Scholar
  43. Jurk M, Kritzler A, Schulte B, Tluk S, Schetter C, Krieg AM, Vollmer J (2006) Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides. Eur J Immunol 36: 1815-1826CrossRefPubMedGoogle Scholar
  44. Kariko K, Buckstein M, Ni H, Weissman D (2005) Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23: 165-175CrossRefPubMedGoogle Scholar
  45. Karlin S, Doerfler W, Cardon LR (1994) Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J Virol 68: 2889-2897PubMedGoogle Scholar
  46. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23: 19-28CrossRefPubMedGoogle Scholar
  47. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis ESC, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. NatureGoogle Scholar
  48. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nature immunology 5: 1061-1068CrossRefPubMedGoogle Scholar
  49. Kierzek E, Kierzek R (2003) The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. Nucleic Acids Res 31: 4472-4480CrossRefPubMedGoogle Scholar
  50. Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20: 709-760CrossRefPubMedGoogle Scholar
  51. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374: 546-549CrossRefPubMedGoogle Scholar
  52. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5: 190-198CrossRefPubMedGoogle Scholar
  53. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A (2005) RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202: 1171-1177CrossRefPubMedGoogle Scholar
  54. Leifer CA, Kennedy MN, Mazzoni A, Lee C, Kruhlak MJ, Segal DM (2004) TLR9 is localized in the endoplasmic reticulum prior to stimulation. J Immunol 173: 1179-1183PubMedGoogle Scholar
  55. Levin AA (1999) A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1489: 69-84PubMedGoogle Scholar
  56. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Nat Acad Sci USA 101: 5598-5603CrossRefPubMedGoogle Scholar
  57. Manoharan M (2004) RNA interference and chemically modified small interfering RNAs. Curr Opin Chem Biol 8: 570-579CrossRefPubMedGoogle Scholar
  58. Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto Y, Yamamoto A, Seya T (2003) Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 171: 3154-3162PubMedGoogle Scholar
  59. Melchjorsen J, Jensen SB, Malmgaard L, Rasmussen SB, Weber F, Bowie AG, Matikainen S, Paludan SR (2005) Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner. J Virol 79: 12944-12951CrossRefPubMedGoogle Scholar
  60. Montagnier L, Sanders FK (1963) Replicative form of encephalomyocarditis virus ribonucleic acid. Nature 199: 664-667CrossRefPubMedGoogle Scholar
  61. Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W, Hartsough K, Machemer L, Radka S, Jadhav V, Vaish N, Zinnen S, Vargeese C, Bowman K, Shaffer CS, Jeffs LB, Judge A, MacLachlan I, Polisky B (2005) Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23: 1002-1007CrossRefPubMedGoogle Scholar
  62. Nishiya T, Kajita E, Miwa S, Defranco AL (2005) TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J Biol Chem 280: 37107-37117CrossRefPubMedGoogle Scholar
  63. Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G (2006) Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439: 208-211CrossRefPubMedGoogle Scholar
  64. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis e Sousa C (2006) RIGI-mediated antiviral responses to single-stranded RNA bearing 5′ -phosphates. Science 314: 997-1001CrossRefPubMedGoogle Scholar
  65. Pieken WA, Olsen DB, Benseler F, Aurup H, Eckstein F (1991) Kinetic characterization of ribonuclease-resistant 2′ -modified hammerhead ribozymes. Science 253: 314-317CrossRefPubMedGoogle Scholar
  66. Riedl P, Stober D, Oehninger C, Melber K, Reimann J, Schirmbeck R (2002) Priming Th1 immunity to viral core particles is facilitated by trace amounts of RNA bound to its arginine-rich domain. J Immunol 168: 4951-4959PubMedGoogle Scholar
  67. Robbins MA, Li M, Leung I, Li H, Boyer DV, Song Y, Behlke MA, Rossi JJ (2006) Stable expression of shRNAs in human CD34+progenitor cells can avoid induction of interferon responses to siRNAs in vitro. Nat Biotechnol 24: 566-571CrossRefPubMedGoogle Scholar
  68. Rozenski J, Crain PF, McCloskey JA (1999) The RNA modification database: 1999 update. Nucleic Acids Res 27: 196-197CrossRefPubMedGoogle Scholar
  69. Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, Bauer S (2004) Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34: 2541-2550CrossRefPubMedGoogle Scholar
  70. Scheel B, Braedel S, Probst J, Carralot JP, Wagner H, Schild H, Jung G, Rammensee HG, Pascolo S (2004) Immunostimulating capacities of stabilized RNA molecules. Eur J Immunol 34: 537-547CrossRefPubMedGoogle Scholar
  71. Sioud M (2006) Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2′ -hydroxyl uridines in immune responses. Eur J Immunol 36: 1222-1230CrossRefPubMedGoogle Scholar
  72. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5: 834-839CrossRefPubMedGoogle Scholar
  73. Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J (2005) Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 23: 709-717CrossRefPubMedGoogle Scholar
  74. Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoharan M, Vornlocher HP (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432: 173-178CrossRefPubMedGoogle Scholar
  75. Sugiyama T, Gursel M, Takeshita F, Coban C, Conover J, Kaisho T, Akira S, Klinman DM, Ishii KJ (2005) CpG RNA: Identification of novel single-stranded RNA that stimulates human CD14 + CD11c+monocytes. J Immunol 174: 2273-2279PubMedGoogle Scholar
  76. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S (2005) Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med 201: 915-923CrossRefPubMedGoogle Scholar
  77. Weissman D, Ni H, Scales D, Dude A, Capodici J, McGibney K, Abdool A, Isaacs SN, Cannon G, Kariko K (2000) HIV gag mRNA transfection of dendritic cells (DC) delivers encoded antigen to MHC class I and II molecules, causes DC maturation, and induces a potent human in vitro primary immune response. J Immunol 165: 4710-4717PubMedGoogle Scholar
  78. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNAinduced innate antiviral responses. Nat Immunol 5: 730-737CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Division of Clinical Pharmacology, Department of Internal MedicineUniversity of MunichMunichGermany
  2. 2.Division of Clinical Pharmacology, University HospitalUniversity of BonnBonnGermany
  3. 3.Institute of Clinical Biochemistry and PharmacologyUniversity Hospital, University of BonnBonnGermany

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