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

Kazuhito Gotoh, Yoshihiko Tanaka, Akihiko Nishikimi, Risa Nakamura, Hisakata Yamada, Naoyoshi Maeda, Takahiro Ishikawa, Katsuaki Hoshino, Takehito Uruno, Qinhong Cao, Sadayuki Higashi, Yasushi Kawaguchi, Munechika Enjoji, Ryoichi Takayanagi, Tsuneyasu Kaisho, Yasunobu Yoshikai, Yoshinori Fukui

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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 tolllike receptors (TLR) 7 and 9, type I IFN induction additionally requires IκB kinase (IKK) α-dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-α activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-α 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-α and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-α 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-α 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.

Original languageEnglish
Pages (from-to)721-730
Number of pages10
JournalJournal of Experimental Medicine
Volume207
Issue number4
DOIs
Publication statusPublished - Apr 12 2010

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Gotoh, K., Tanaka, Y., Nishikimi, A., Nakamura, R., Yamada, H., Maeda, N., Ishikawa, T., Hoshino, K., Uruno, T., Cao, Q., Higashi, S., Kawaguchi, Y., Enjoji, M., Takayanagi, R., Kaisho, T., Yoshikai, Y., & Fukui, Y. (2010). Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation. Journal of Experimental Medicine, 207(4), 721-730. https://doi.org/10.1084/jem.20091776