TLR8 deficiency leads to autoimmunity in mice
Olivier Demaria, … , Richard A. Flavell, Lena Alexopoulou
Olivier Demaria, … , Richard A. Flavell, Lena Alexopoulou
Published September 1, 2010
Citation Information: J Clin Invest. 2010;120(10):3651-3662. https://doi.org/10.1172/JCI42081.
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Research Article Autoimmunity

TLR8 deficiency leads to autoimmunity in mice

Abstract

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.

Authors

Olivier Demaria, Philippe P. Pagni, Stephanie Traub, Aude de Gassart, Nora Branzk, Andrew J. Murphy, David M. Valenzuela, George D. Yancopoulos, Richard A. Flavell, Lena Alexopoulou

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Figure 1

Targeted disruption of the mouse Tlr8 gene.

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Targeted disruption of the mouse Tlr8 gene. (A) PCR analysis of mous...
(A) PCR analysis of mouse genomic DNA with specific primers gave a 240-bp band for Tlr8+/+ mice, a 589-bp band for Tlr8–/– mice, and both bands for Tlr8+/– mice. M, molecular weight marker (100-bp DNA ladder; Invitrogen). (B) Expression of Tlr8 and Hprt mRNA by WT and Tlr8–/– BMDCs either untreated or stimulated with 50 nM R848 or 1 ng/ml LPS for 4 hours, as determined by RT-PCR. (C) Northern blot analysis of RNA from untreated, 1 ng/ml LPS–, or 50 nM R848–stimulated WT and Tlr8–/– BMDCs. Ethidium bromide staining after RNA transfer to the membrane is included as control (bottom). (D) Reporter gene expression (LacZ reporter, blue) in spleen and mesenteric lymph node sections from Tlr8–/– mice. (A–D) Data are representative of 2–4 independent experiments.