U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7.
Plasmacytoid dendritic cells (PDCs), which produce IFN-alpha in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-alpha and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-alpha and IL-6 by U1snRNPs in murine bone marrow-derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-alpha and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous "self" ligand for Tlr7 and triggers IFN-alpha and IL-6 production in PDCs.
Savarese
Emina
E
Department of Internal Medicine, Technical University Munich, Germany.
Chae
Ohk-wha
OW
Trowitzsch
Simon
S
Weber
Gert
G
Kastner
Berthold
B
Akira
Shizuo
S
Wagner
Hermann
H
Schmid
Roland M
RM
Bauer
Stefan
S
Krug
Anne
A
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology* / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009843:Oligoribonucleotides / Q000276:immunology / Q000494:pharmacology; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology* / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000276:immunology*; D051941:fms-Like Tyrosine Kinase 3 / Q000276:immunology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D016898:Interferon-alpha; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009843:Oligoribonucleotides; D017412:Ribonucleoprotein, U1 Small Nuclear; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3