Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.
Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN-alpha production. Localization of the immunostimulatory motif on the sense strand of a potent IFN-alpha-inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).
Hornung
Veit
V
Department of Internal Medicine, Division of Clinical Pharmacology, Ludwig-Maximilians-University of Munich, Ziemssenstr. 1, 80336 München, Germany.
Guenthner-Biller
Margit
M
Bourquin
Carole
C
Ablasser
Andrea
A
Schlee
Martin
M
Uematsu
Satoshi
S
Noronha
Anne
A
Manoharan
Muthiah
M
Akira
Shizuo
S
de Fougerolles
Antonin
A
Endres
Stefan
S
Hartmann
Gunther
G
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis*; D008081:Liposomes; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D034741:RNA, Small Interfering / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D012367:RNA, Viral / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D016898:Interferon-alpha; D008081:Liposomes; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011956:Receptors, Cell Surface; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors