Toll-Like Receptor 9 Deficiency Breaks Tolerance to RNA-Associated Antigens and Up-Regulates Toll-Like Receptor 7 Protein in Sle1 Mice

Teja Celhar, Hiroko Yasuga, Hui Yin Lee, Olga Zharkova, Shubhita Tripathi, Susannah I. Thornhill, Hao K. Lu, Bijin Au, Lina H.K. Lim, Thomas P. Thamboo, Shizuo Akira, Edward K. Wakeland, John E. Connolly, Anna Marie Fairhurst

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Objective: Toll-like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of systemic lupus erythematosus (SLE). While multiple studies support the notion of a dependency on TLR-7 for disease development, genetic ablation of TLR-9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. This study was undertaken to examine the suppressive role of TLR-9 in the development of severe lupus in a mouse model. Methods: We crossed Sle1 lupus-prone mice with TLR-9–deficient mice to generate Sle1TLR-9−/− mice. Mice ages 4.5–6.5 months were evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total Ig profiles, kidney dendritic cell (DC) function, and TLR-7 protein expression. Mice ages 8–10 weeks were used for functional B cell studies, Ig profiling, and determination of TLR-7 expression. Results: Sle1TLR-9−/− mice developed severe disease similar to TLR-9–deficient MRL and Nba2 models. Sle1TLR-9−/− mouse B cells produced more class-switched antibodies, and the autoantibody repertoire was skewed toward RNA-containing antigens. GN in these mice was associated with DC infiltration, and purified Sle1TLR-9−/− mouse renal DCs were more efficient at TLR-7–dependent antigen presentation and expressed higher levels of TLR-7 protein. Importantly, this increase in TLR-7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction. Conclusion: The increase in TLR-7–reactive immune complexes, and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1TLR9−/− mice.

Original languageEnglish (US)
Pages (from-to)1597-1609
Number of pages13
JournalArthritis and Rheumatology
Volume70
Issue number10
DOIs
StatePublished - Oct 1 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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    Celhar, T., Yasuga, H., Lee, H. Y., Zharkova, O., Tripathi, S., Thornhill, S. I., Lu, H. K., Au, B., Lim, L. H. K., Thamboo, T. P., Akira, S., Wakeland, E. K., Connolly, J. E., & Fairhurst, A. M. (2018). Toll-Like Receptor 9 Deficiency Breaks Tolerance to RNA-Associated Antigens and Up-Regulates Toll-Like Receptor 7 Protein in Sle1 Mice. Arthritis and Rheumatology, 70(10), 1597-1609. https://doi.org/10.1002/art.40535