TLR8 deficiency leads to autoimmunity in mice.
TLRs play an essential role in the induction of immune responses by detecting conserved molecular products of microorganisms. However, the function of TLR8 is largely unknown. In the current study, we investigated the role of TLR8 signaling in immunity in mice. We found that Tlr8(-/-) DCs overexpressed TLR7, were hyperresponsive to various TLR7 ligands, and showed stronger and faster NF-κB activation upon stimulation with the TLR7 ligand R848. Tlr8(-/-) mice showed splenomegaly, defective development of marginal zone (MZ) and B1 B cells, and increased serum levels of IgM and IgG2a. Furthermore, Tlr8(-/-) mice exhibited increased serum levels of autoantibodies against small nuclear ribonucleoproteins, ribonucleoprotein, and dsDNA and developed glomerulonephritis, whereas neither Tlr7(-/-) nor Tlr8(-/-)Tlr7(-/-) mice showed any of the phenotypes observed in Tlr8(-/-) mice. These data provide evidence for a pivotal role for mouse TLR8 in the regulation of mouse TLR7 expression and prevention of spontaneous autoimmunity.
Demaria
Olivier
O
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Marseille, France.
Pagni
Philippe P
PP
Traub
Stephanie
S
de Gassart
Aude
A
Branzk
Nora
N
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Yancopoulos
George D
GD
Flavell
Richard A
RA
Alexopoulou
Lena
L
D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D008562:Membrane Glycoproteins; D016328:NF-kappa B; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8
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