Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells.
Stimulation of dendritic cells (DCs) by the egg stage of the helminth parasite Schistosoma mansoni activates a signaling pathway resulting in type I interferon (IFN) and IFN-stimulated gene (ISG) expression. Here, we demonstrate that S. mansoni eggs disjointedly activate myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways in DCs. Inflammatory cytokine expression and NF-kappa B activation in DCs from MyD88-deficient mice were impaired, whereas signaling transducer activator of transcription (STAT) 1(Tyr701) phosphorylation and ISG expression were intact in MyD88 or Toll-like receptor (TLR)4-deficient counterparts. Accordingly, we analyzed distinct TLR members for their ability to respond to schistosome eggs and established that TLR3 resulted in the activation of NF-kappa B and the positive regulatory domain III-I site from IFN-beta promoter. Unexpectedly, egg-derived RNA possessed RNase A-resistant and RNase III-sensitive structures capable of triggering TLR3 activation, suggesting the involvement of double-stranded (ds) structures. Moreover, DCs from TLR3-deficient mice displayed a complete loss of signaling transducer activator of transcription 1 phosphorylation and ISG expression in response to egg-derived dsRNA. Finally, TLR3-deficient DCs showed a reduced response to schistosome eggs relative to wild-type cells. Collectively, our data suggest for the first time that dsRNA from a non-viral pathogen may act as an inducer of the innate immune system through TLR3.
Aksoy
Ezra
E
INSERM U547, Institut Pasteur de Lille, Lille 59019, France.
Zouain
Claudia S
CS
Vanhoutte
François
F
Fontaine
Josette
J
Pavelka
Norman
N
Thieblemont
Nathalie
N
Willems
Fabienne
F
Ricciardi-Castagnoli
Paola
P
Goldman
Michel
M
Capron
Monique
M
Ryffel
Bernard
B
Trottein
François
F
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D012330:RNA, Double-Stranded / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D012547:Schistosoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012552:Schistosomiasis / Q000276:immunology / Q000378:metabolism*; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors