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

被引：92

作者：

Gotoh, Kazuhito ^{[1
,3
]}

Tanaka, Yoshihiko ^{[1
,4
]}

Nishikimi, Akihiko ^{[1
,4
]}

Nakamura, Risa ^{[2
]}

Yamada, Hisakata ^{[2
]}

Maeda, Naoyoshi ^{[2
]}

Ishikawa, Takahiro ^{[2
]}

Hoshino, Katsuaki ^{[5
]}

Uruno, Takehito ^{[1
]}

Cao, Qinhong ^{[1
]}

Higashi, Sadayuki ^{[1
,4
]}

Kawaguchi, Yasushi ^{[6
]}

Enjoji, Munechika ^{[3
]}

Takayanagi, Ryoichi ^{[3
]}

Kaisho, Tsuneyasu ^{[5
]}

Yoshikai, Yasunobu ^{[2
]}

Fukui, Yoshinori ^{[1
,4
]}

机构：

[1] Kyushu Univ, Grad Sch Med Sci, Dept Immunobiol & Neurosci, Div Immunogenet, Fukuoka 8128582, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Div Host Def, Res Ctr Prevent Infect Dis,Med Inst Bioregulat, Fukuoka 8128582, Japan

[3] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 8128582, Japan

[4] Japan Sci & Technol Agcy, Tokyo 1020075, Japan

[5] RIKEN, Host Def Lab, Res Ctr Allergy & Immunol, Kanagawa 2300045, Japan

[6] Univ Tokyo, Div Viral Infect, Dept Infect Dis Control, Int Res Ctr Infect Dis,Inst Med Sci, Tokyo 1088639, Japan

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2010年 / 207卷 / 04期

基金：

日本科学技术振兴机构;

关键词：

INTERFERON-ALPHA PRODUCTION; NEUTROPHIL CHEMOTAXIS; LYMPHOCYTE MIGRATION; PREDENDRITIC CELLS; PROTEIN DOCK2; BACTERIAL-DNA; CPG MOTIFS; KAPPA-B; RECOGNITION; MOTILITY;

D O I：

10.1084/jem.20091776

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 I. B 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.

引用

页码：721 / 730

页数：10