| Autor: |
Panda SK; MedImmune, Gaithersburg, Maryland, USA.; Baylor Institute for Immunology Research, Dallas, Texas, USA., Facchinetti V; MD Anderson Cancer Center, Houston, Texas, USA., Voynova E; MedImmune, Gaithersburg, Maryland, USA., Hanabuchi S; MedImmune, Gaithersburg, Maryland, USA.; Baylor Institute for Immunology Research, Dallas, Texas, USA., Karnell JL; MedImmune, Gaithersburg, Maryland, USA., Hanna RN; MedImmune, Gaithersburg, Maryland, USA., Kolbeck R; MedImmune, Gaithersburg, Maryland, USA., Sanjuan MA; MedImmune, Gaithersburg, Maryland, USA., Ettinger R; MedImmune, Gaithersburg, Maryland, USA., Liu YJ; MedImmune, Gaithersburg, Maryland, USA.; Baylor Institute for Immunology Research, Dallas, Texas, USA.; MD Anderson Cancer Center, Houston, Texas, USA. |
| Abstrakt: |
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. |
