Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation

J Exp Med. 2010 Apr 12;207(4):721-30. doi: 10.1084/jem.20091776. Epub 2010 Mar 15.

Abstract

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IkappaB kinase (IKK) alpha-dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-alpha activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-alpha induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-alpha and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-alpha induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2-Rac signaling pathway acts in parallel with TLR engagement to control IKK-alpha activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN-related autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Endosomes / metabolism
  • Female
  • GTPase-Activating Proteins / metabolism*
  • Herpesvirus 2, Human / immunology
  • I-kappa B Kinase / metabolism
  • Imidazoles / pharmacology
  • Influenza A virus / immunology
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / biosynthesis*
  • Interferon Type I / metabolism
  • Interferon-alpha / blood
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology
  • Interferon-beta / metabolism
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Interleukin-12 Subunit p40 / blood
  • Interleukin-12 Subunit p40 / metabolism
  • Male
  • Membrane Glycoproteins / agonists
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Oligodeoxyribonucleotides / metabolism
  • Oligodeoxyribonucleotides / pharmacology
  • Phosphorylation / drug effects
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / metabolism
  • Toll-Like Receptors / agonists
  • Toll-Like Receptors / immunology*
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein

Substances

  • Actins
  • CPG-oligonucleotide
  • DOCK2 protein, mouse
  • GTPase-Activating Proteins
  • Imidazoles
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Interferon-alpha
  • Interleukin-12 Subunit p40
  • Irf7 protein, mouse
  • Membrane Glycoproteins
  • Neuropeptides
  • Oligodeoxyribonucleotides
  • Rac1 protein, mouse
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tlr7 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Interferon-beta
  • Interleukin-1 Receptor-Associated Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Mitogen-Activated Protein Kinases
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • resiquimod