Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models
| Autor: | Yong-Jun Liu, Jodi L. Karnell, Santosh K. Panda, Miguel A. Sanjuan, Shino Hanabuchi, Elisaveta Voynova, Rachel Ettinger, Richard N. Hanna, Roland Kolbeck, Valeria Facchinetti |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Galectins medicine.medical_treatment medicine.disease_cause Autoimmunity Mice 03 medical and health sciences 0302 clinical medicine immune system diseases medicine Animals Humans Lupus Erythematosus Systemic PI3K/AKT/mTOR pathway Autoantibodies Galectin B-Lymphocytes Membrane Glycoproteins Systemic lupus erythematosus Chemistry TOR Serine-Threonine Kinases Autoantibody Ribosomal Protein S6 Kinases 70-kDa TLR9 hemic and immune systems Dendritic Cells General Medicine TLR7 medicine.disease Disease Models Animal 030104 developmental biology Cytokine Toll-Like Receptor 7 Toll-Like Receptor 9 Immunology Female Research Article Signal Transduction 030215 immunology |
| Zdroj: | Journal of Clinical Investigation. 128:1873-1887 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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