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Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models
Santosh K. Panda, … , Rachel Ettinger, Yong-Jun Liu
Santosh K. Panda, … , Rachel Ettinger, Yong-Jun Liu
Published April 3, 2018
Citation Information: J Clin Invest. 2018;128(5):1873-1887. https://doi.org/10.1172/JCI97333.
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Research Article Immunology Inflammation Article has an altmetric score of 6

Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models

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Abstract

Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap–mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

Authors

Santosh K. Panda, Valeria Facchinetti, Elisaveta Voynova, Shino Hanabuchi, Jodi L. Karnell, Richard N. Hanna, Roland Kolbeck, Miguel A. Sanjuan, Rachel Ettinger, Yong-Jun Liu

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Figure 2

Administration of Gal-9 impairs the expansion and activation of T cells.

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Administration of Gal-9 impairs the expansion and activation of T cells....
Splenocytes from male BXSB/MpJ mice with and without Gal-9 treatment and female littermates of 19 weeks of age were analyzed. Representative flow cytometric figures of the expression of CD44 and CD62L on CD4+ T cells (A) and CD8+ T cells (C). Frequency of CD44hiCD62Llo and CD44loCD62Lhi cells on CD4+ T cells (B) and CD8+ T cells (D), as analyzed by flow cytometry. Data points represent individual mice. n = 10. Data are representative of 2 independent experiments and are shown as mean ± SD. One-way ANOVA with Dunnett’s multiple comparison was used to test statistical significance. *P < 0.05; **P < 0.01; ***P < 0.001 versus control; ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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