Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models
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
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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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 3

Gal-9 administration inhibits ABC and T2B cell expansion, reconstitutes MZB and T1 B cells, and limits autoantibody generation in male BXSB/MpJ mice.

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Gal-9 administration inhibits ABC and T2B cell expansion, reconstitutes ...
Splenocytes from Gal-9–treated male, untreated male, and age-matched female littermates were analyzed for expression of different markers on CD19+ B cells. (A) Representative flow plots of CD23 and CD21 expression on splenic B cells. (B) Frequency of CD23–CD21hi MZB cells and CD23–CD21–AA4.1– ABCs were analyzed by FACS. (C) Representative graphs of (CD21–, CD23–, IgM+, and IgDlo) T1 cells and (CD21–, CD23–, IgM+, and IgDhi) T2 cells. (D) Frequency of T1 cells and T2 cells was analyzed by FACS. Data points represent individual mice. Data are shown as mean ± SD. (E) Serum of male BXSB/MpJ mice treated with Gal-9 along with untreated control and age-matched female littermates were analyzed for levels of IgG and IgG2c against nuclear autoantigens by ELISA. 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 the statistical significance for data presented in C and D, and Kruskal-Wallis testing was performed followed by Dunn’s test for E. *P < 0.05; **P < 0.01; ***P < 0.001 versus control; ****P < 0.0001.