Regulatory role of SphK1 in TLR7/9‐dependent type I interferon response and autoimmunity

Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1‐phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro‐inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane‐induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN‐linked autoimmune disorders.

[1]  S. Spiegel,et al.  Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  V. Soumelis,et al.  Plasmacytoid pre-dendritic cells (pDC): from molecular pathways to function and disease association. , 2018, Seminars in cell & developmental biology.

[3]  K. Harikumar,et al.  Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine , 2018, Theranostics.

[4]  S. Milstien,et al.  TP53 is required for BECN1- and ATG5-dependent cell death induced by sphingosine kinase 1 inhibition , 2018, Autophagy.

[5]  D. Olive,et al.  The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells , 2018, Front. Immunol..

[6]  O. Monticielo,et al.  Pristane-induced lupus: considerations on this experimental model , 2017, Clinical Rheumatology.

[7]  J. N. Clarke,et al.  Investigation of sphingosine kinase 1 in interferon responses during dengue virus infection , 2017, Clinical & translational immunology.

[8]  Georg Schett,et al.  Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. , 2017, JCI insight.

[9]  G. Gilkeson,et al.  Plasmacytoid dendritic cell distribution and maturation are altered in lupus prone mice prior to the onset of clinical disease. , 2017, Clinical immunology.

[10]  K. Kalunian,et al.  Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus , 2017, Arthritis & rheumatology.

[11]  M. Maceyka,et al.  FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann‐Pick type C mutant fibroblasts , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  S. Milstien,et al.  Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking* , 2017, The Journal of Biological Chemistry.

[13]  Hong-Gang Wang,et al.  Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking. , 2016, Cell reports.

[14]  P. Tewary,et al.  IRF5 and IRF8 modulate the CAL‐1 human plasmacytoid dendritic cell line response following TLR9 ligation , 2016, European journal of immunology.

[15]  Li Wu,et al.  Phenotypic and functional alterations of pDCs in lupus-prone mice , 2016, Scientific Reports.

[16]  B. Brüne,et al.  S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-α Production by Human Plasmacytoid Dendritic Cells , 2016, The Journal of Immunology.

[17]  T. Taniguchi,et al.  S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification , 2016, Proceedings of the National Academy of Sciences.

[18]  X. Liao,et al.  Cutting Edge: Plasmacytoid Dendritic Cells in Late-Stage Lupus Mice Defective in Producing IFN-α , 2015, The Journal of Immunology.

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

[20]  C. Szeto,et al.  Animal Models of Interferon Signature Positive Lupus , 2015, Front. Immunol..

[21]  C. Mathews,et al.  Mechanisms of Tumor Necrosis Factor α Antagonist–Induced Lupus in a Murine Model , 2015, Arthritis & rheumatology.

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

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

[24]  Sarah Spiegel,et al.  Sphingolipid metabolites in inflammatory disease , 2014, Nature.

[25]  J. Pers,et al.  TLR9 expressed on plasma membrane acts as a negative regulator of human B cell response. , 2014, Journal of autoimmunity.

[26]  P. De Camilli,et al.  Coupling between endocytosis and sphingosine kinase I recruitment , 2014, Nature Cell Biology.

[27]  Y. Seo,et al.  Sphingosine kinase 1 regulates measles virus replication. , 2014, Virology.

[28]  D. Isenberg,et al.  Systemic lupus erythematosus , 1956, The Lancet.

[29]  S. Milstien,et al.  Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond , 2013, Nature Reviews Drug Discovery.

[30]  T. Taniguchi,et al.  The IRF family transcription factors at the interface of innate and adaptive immune responses. , 2013, Cold Spring Harbor symposia on quantitative biology.

[31]  A. Theofilopoulos.  TLRs and IFNs: critical pieces of the autoimmunity puzzle. , 2012, The Journal of clinical investigation.

[32]  J. Agrewala,et al.  Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni, Vidi, Vici!! , 2012, PLoS pathogens.

[33]  S. Marks,et al.  Increased Serum Concentration of Sphingosine-1-phosphate in Juvenile-onset Systemic Lupus Erythematosus , 2012, Journal of Clinical Immunology.

[34]  T. Kasten,et al.  Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. , 2012, The Biochemical journal.

[35]  Sarah Spiegel,et al.  Sphingosine-1-phosphate signaling and its role in disease. , 2012, Trends in cell biology.

[36]  S. Venz,et al.  Nephrotic Syndrome and Subepithelial Deposits in a Mouse Model of Immune-Mediated Anti-Podocyte Glomerulonephritis , 2011, The Journal of Immunology.

[37]  S. Akira,et al.  Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. , 2011, Immunity.

[38]  N. Kato,et al.  The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. , 2011, Gastroenterology.

[39]  H. Ploegh,et al.  Granulin is a soluble cofactor for toll-like receptor 9 signaling. , 2011, Immunity.

[40]  Jing Ma,et al.  The sphingosine-1-phosphate receptor agonist FTY720 prevents the development of anti-glomerular basement membrane glomerulonephritis , 2011, Molecular Biology Reports.

[41]  Y. Seo,et al.  Sphingosine 1-Phosphate-Metabolizing Enzymes Control Influenza Virus Propagation and Viral Cytopathogenicity , 2010, Journal of Virology.

[42]  Y. Takasaki,et al.  FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice. , 2010, Biochemical and biophysical research communications.

[43]  M. Satoh,et al.  Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. , 2009, Trends in immunology.

[44]  S. Milstien,et al.  Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. , 2009, Cancer research.

[45]  S. Akira,et al.  TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus , 2008, The Journal of experimental medicine.

[46]  I. McInnes,et al.  Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis1 , 2008, The Journal of Immunology.

[47]  Barbara S. Paugh,et al.  A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. , 2008, Blood.

[48]  K. Takatsu,et al.  A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses , 2007, The Journal of experimental medicine.

[49]  R. Medzhitov,et al.  Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. , 2006, Immunity.

[50]  Chandra Mohan,et al.  Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. , 2005, The Journal of clinical investigation.

[51]  R. Förster,et al.  Sphingosine-1-Phosphate Mediates Migration of Mature Dendritic Cells1 , 2005, The Journal of Immunology.

[52]  Hideo Negishi,et al.  IRF-7 is the master regulator of type-I interferon-dependent immune responses , 2005, Nature.

[53]  M. Tomonaga,et al.  A Novel Plasmacytoid Dendritic Cell Line, CAL-1, Established from a Patient with Blastic Natural Killer Cell Lymphoma , 2005, International journal of hematology.

[54]  R. Proia,et al.  Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 , 2004, Nature.

[55]  M. Vadas,et al.  Activation of sphingosine kinase 1 by ERK1/2‐mediated phosphorylation , 2003, The EMBO journal.

[56]  Guo-Ping Zhou,et al.  Triggering the Interferon Antiviral Response Through an IKK-Related Pathway , 2003, Science.

[57]  H. Iwasaki,et al.  CpG‐DNA‐induced IFN‐α production involves p38 MAPK‐dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors , 2002, Journal of leukocyte biology.

[58]  T. Okada,et al.  Identification and Characterization of RPK118, a Novel Sphingosine Kinase-1-binding Protein* , 2002, The Journal of Biological Chemistry.

[59]  T. Giese,et al.  Quantitative Expression of Toll-Like Receptor 1–10 mRNA in Cellular Subsets of Human Peripheral Blood Mononuclear Cells and Sensitivity to CpG Oligodeoxynucleotides1 , 2002, The Journal of Immunology.

[60]  A. Fujimura,et al.  Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus. , 2002, The Journal of rheumatology.

[61]  Marc Dalod,et al.  Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology , 2001, Nature Immunology.

[62]  C. Maliszewski,et al.  Generation of murine dendritic cells from flt3-ligand-supplemented bone marrow cultures. , 2000, Blood.

[63]  N. Kadowaki,et al.  The nature of the principal type 1 interferon-producing cells in human blood. , 1999, Science.

[64]  M. Satoh,et al.  Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane , 1994, The Journal of experimental medicine.

[65]  J. Goust,et al.  Systemic lupus erythematosus. , 1976, Immunology series.