The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily.
Loxoribine (7-allyl-7,8-dihydro-8-oxo-guanosine) acts as synthetic adjuvant in anti-tumor responses. Here we first demonstrate that loxoribine activates cells of the innate immune system selectively via the Toll-like receptor (TLR) 7/MyD88-dependent signaling pathway. TLR7- and MyD88-deficient immune cells fail to proliferate or produce cytokines in response to loxoribine, and genetic complementation of TLR7-deficient cells with murine or human TLR7 confers responsiveness. Subsequently we show that cellular activation by loxoribine and resiquimod (R-848), a stimulus for TLR7 and TLR8, depends on acidification and maturation of endosomes and targets MyD88 to vesicular structures with lysosomal characteristics. This mode of TLR7 and TLR8 action resembles CpG-DNA-driven TLR9 activation. We thus conclude that TLR7, 8 and 9 form a functional subgroup within the TLR family that recognizes pathogen-associated molecular patterns in endosomal/lysosomal compartments.
Institute for Medical Microbiology, Hygiene and Immunology, Munich, Germany.
Florian
F
Heil
Parviz
P
Ahmad-Nejad
Hiroaki
H
Hemmi
Hubertus
H
Hochrein
Franziska
F
Ampenberger
Tanja
T
Gellert
Harald
H
Dietrich
Grayson
G
Lipford
Kiyoshi
K
Takeda
Shizuo
S
Akira
Hermann
H
Wagner
Stefan
S
Bauer
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D005810:Multigene Family / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism; D013154:Spleen / Q000187:drug effects; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D007093:Imidazoles; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D008934:Mitogens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D006151:Guanosine; C068562:loxoribine; C402365:resiquimod