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 8

Gal-9 inhibits the IC- and NET-induced production of IFN-α, TNF-α, and IL-6 by pDCs.

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Gal-9 inhibits the IC- and NET-induced production of IFN-α, TNF-α, and I...
Human pDCs in the presence or absence of Gal-9 were stimulated with (A) IgG ICs isolated from the sera of SLE pediatric patients or (B) 30% culture supernatants from NET exposed to SLE-derived anti-RNP IgG. Culture supernatants were analyzed for IFN-α, TNF-α, and IL-6. Data shown are mean of 5 to 6 (A) and 3 (B) independent experiments without Gal-9. Unpaired Student’s t test or Mann-Whitney U test with Welch’s correction was used to test statistical significance. *P < 0.05; ***P < 0.001 versus control.