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

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.

[1]  B. Ueberheide,et al.  Dectin-1 Activation on Macrophages by Galectin-9 Promotes Pancreatic Carcinoma and Peritumoral Immune-Tolerance , 2017, Nature Medicine.

[2]  Michael A. Smith,et al.  Self-reactive IgE exacerbates interferon responses associated with autoimmunity , 2015, Nature Immunology.

[3]  M. Colonna,et al.  The multifaceted biology of plasmacytoid dendritic cells , 2015, Nature Reviews Immunology.

[4]  E. Unanue,et al.  Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model , 2014, The Journal of experimental medicine.

[5]  V. D’Agati,et al.  Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus , 2014, The Journal of experimental medicine.

[6]  S. Yokoyama,et al.  The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. , 2014, Immunity.

[7]  Chuan Wu,et al.  Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. , 2014, Immunity.

[8]  T. Imanishi‐Kari,et al.  Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells , 2013, The Journal of experimental medicine.

[9]  T. Niki,et al.  Galectin-9 Ameliorates Clinical Severity of MRL/lpr Lupus-Prone Mice by Inducing Plasma Cell Apoptosis Independently of Tim-3 , 2013, PloS one.

[10]  A. Rieger,et al.  TIM-3 Does Not Act as a Receptor for Galectin-9 , 2013, PLoS pathogens.

[11]  B. Palmer,et al.  Galectin-9 Functionally Impairs Natural Killer Cells in Humans and Mice , 2013, Journal of Virology.

[12]  R. Schreiber,et al.  Anti–IFN-α/β Receptor Antibody Treatment Ameliorates Disease in Lupus-Predisposed Mice , 2012, The Journal of Immunology.

[13]  T. Niki,et al.  Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner. , 2012, Clinical immunology.

[14]  V. Kuchroo,et al.  T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses , 2011, Proceedings of the National Academy of Sciences.

[15]  P. Marrack,et al.  Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c⁺ B-cell population is important for the development of autoimmunity. , 2011, Blood.

[16]  Benhur Lee,et al.  Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry , 2011, Proceedings of the National Academy of Sciences.

[17]  A. Marshak‐Rothstein,et al.  Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. , 2011, Seminars in immunology.

[18]  J. Huber,et al.  Regulation of effector and memory T‐cell functions by type I interferon , 2011, Immunology.

[19]  B. Reizis,et al.  Plasmacytoid dendritic cells: recent progress and open questions. , 2011, Annual review of immunology.

[20]  J. Connolly,et al.  Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus , 2011, Science Translational Medicine.

[21]  Y. Zou,et al.  Plasma cells in systemic lupus erythematosus: The long and short of it all , 2011, European journal of immunology.

[22]  T. Phan,et al.  Clearing the complexity: immune complexes and their treatment in lupus nephritis , 2011, International journal of nephrology and renovascular disease.

[23]  V. Kuchroo,et al.  Tim3 binding to galectin-9 stimulates antimicrobial immunity , 2010, The Journal of experimental medicine.

[24]  A. Yamauchi,et al.  Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway. , 2010, Biochemical and biophysical research communications.

[25]  T. Niki,et al.  Galectin-9 ameliorates immune complex-induced arthritis by regulating Fc gamma R expression on macrophages. , 2009, Clinical immunology.

[26]  T. Niki,et al.  Galectin-9 Is a High Affinity IgE-binding Lectin with Anti-allergic Effect by Blocking IgE-Antigen Complex Formation , 2009, The Journal of Biological Chemistry.

[27]  F. Schmitz,et al.  Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells , 2008, European journal of immunology.

[28]  B. Pulendran,et al.  Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway , 2008, Nature Immunology.

[29]  L. Bourguignon.  Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. , 2008, Seminars in cancer biology.

[30]  John E. Connolly,et al.  Systemic IFN‐α drives kidney nephritis in B6.Sle123 mice , 2008, European journal of immunology.

[31]  V. Pascual,et al.  The innate immune system in SLE: type I interferons and dendritic cells , 2008, Lupus.

[32]  T. Niki,et al.  Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. , 2008, Clinical immunology.

[33]  S. Grinstein,et al.  CD44-mediated phagocytosis induces inside-out activation of complement receptor-3 in murine macrophages. , 2007, Blood.

[34]  R. Coffman,et al.  Treatment of lupus‐prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms , 2007, European journal of immunology.

[35]  T. Niki,et al.  Galectin-9 inhibits CD44-hyaluronan interaction and suppresses a murine model of allergic asthma. , 2007, American journal of respiratory and critical care medicine.

[36]  Alex K. Heer,et al.  TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses1 , 2007, The Journal of Immunology.

[37]  X. Qin,et al.  Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand , 2007, The Journal of experimental medicine.

[38]  A. Marshak‐Rothstein.  Toll-like receptors in systemic autoimmune disease , 2006, Nature Reviews Immunology.

[39]  V. Pascual,et al.  Type I interferon in systemic lupus erythematosus and other autoimmune diseases. , 2006, Immunity.

[40]  Wei Cao,et al.  Plasmacytoid dendritic cell–specific receptor ILT7–FcɛRIγ inhibits Toll-like receptor–induced interferon production , 2006, The Journal of experimental medicine.

[41]  V. Kuchroo,et al.  The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity , 2005, Nature Immunology.

[42]  R. Hoffman,et al.  T cells in the pathogenesis of systemic lupus erythematosus. , 2004, Frontiers in bioscience : a journal and virtual library.

[43]  M. Hirashima,et al.  Double‐stranded RNA enhances the expression of galectin‐9 in vascular endothelial cells , 2004, Immunology and cell biology.

[44]  B. Toole,et al.  Hyaluronan: from extracellular glue to pericellular cue , 2004, Nature Reviews Cancer.

[45]  C. Isacke,et al.  The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events , 2003, Journal of Cell Science.

[46]  Virginia Pascual,et al.  Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. , 2003, Immunity.

[47]  D. Choubey,et al.  Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB Mice , 2003, The Journal of experimental medicine.

[48]  G. Karypis,et al.  Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Musheng Bao,et al.  Regulation of TLR7/9 signaling in plasmacytoid dendritic cells , 2012, Protein & Cell.

[50]  Jian-nan Feng,et al.  The N- and C-terminal carbohydrate recognition domains of galectin-9 contribute differently to its multiple functions in innate immunity and adaptive immunity. , 2011, Molecular immunology.

[51]  M. Clare-Salzler,et al.  Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases , 2009 .

[52]  Wei Cao,et al.  Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production , 2006 .

[53]  A. Aderem,et al.  TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE. , 2006, The Journal of experimental medicine.

[54]  A. Aderem,et al.  TLR 9 / MyD 88 signaling is required for class switching to pathogenic IgG 2 a and 2 b autoantibodies in SLE , 2006 .

[55]  Gabriel A. Rabinovich,et al.  Galectins as modulators of tumour progression , 2005, Nature Reviews Cancer.

[56]  A. Yamauchi,et al.  Galectin-9 in physiological and pathological conditions , 2004, Glycoconjugate Journal.

[57]  B. Pulendran,et al.  Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI ( 3 ) K-mTOR-p 70 S 6 K pathway , 2022 .