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

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

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 1

Splenomegaly and hyperplasia in the spleens of male BXSB/MpJ mice are inhibited with Gal-9 treatment.

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Splenomegaly and hyperplasia in the spleens of male BXSB/MpJ mice are in...
Male BXSB/MpJ mice were treated with Gal-9 from 8 to 18 weeks; the spleens were collected at 19 weeks and analyzed. (A) Representative images of the size of the spleens. (B) Histograms showing the weight of the spleens, the total number of splenocytes, (C) B cells (CD19+), T cells (CD3+), and T helper cells (CD4+). Data points represent individual mice. (D) Representative flow plots of pDC staining and the percentage of pDCs in the spleens of Gal-9–treated males and untreated male and female littermates. (E) A representative histogram of the expression of CD86 on pDCs and percentage of CD86-expressing pDCs of Gal-9–treated males, untreated males, and female littermates. Data are shown as mean ± SD. n = 10. Data are representative of 2 independent experiments. One-way ANOVA with Dunnett’s multiple comparison was used to test the statistical significance for all the data. For E, Kruskal-Wallis testing was performed, followed by Dunn’s test. *P < 0.05; **P < 0.01; ***P < 0.001 versus control; ****P < 0.0001.