DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation

Mayuki Watanabe, Masao Terasawa, Kei Miyano, Toyoshi Yanagihara, Takehito Uruno, Fumiyuki Sanematsu, Akihiko Nishikimi, Jean François Côté, Hideki Sumimoto, Yoshinori Fukui

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Neutrophils are highly motile leukocytes that play important roles in the innate immune response to invading pathogens. Neutrophils rapidly migrate to the site of infections and kill pathogens by producing reactive oxygen species (ROS). Neutrophil chemotaxis and ROS production require activation of Rac small GTPase. DOCK2, an atypical guanine nucleotide exchange factor (GEF), is one of the major regulators of Rac in neutrophils. However, because DOCK2 deficiency does not completely abolish fMLF-induced Rac activation, other Rac GEFs may also participate in this process. In this study, we show that DOCK5 acts with DOCK2 in neutrophils to regulate multiple cellular functions. We found that fMLF- and PMA-induced Rac activation were almost completely lost in mouse neutrophils lacking both DOCK2 and DOCK5. Although β2 integrin-mediated adhesion occurred normally even in the absence of DOCK2 and DOCK5, mouse neutrophils lacking DOCK2 and DOCK5 exhibited a severe defect in chemotaxis and ROS production. Similar results were obtained when human neutrophils were treated with CPYPP, a small-molecule inhibitor of these DOCK GEFs. Additionally, we found that DOCK2 and DOCK5 regulate formation of neutrophil extracellular traps (NETs). Because NETs are involved in vascular inflammation and autoimmune responses, DOCK2 and DOCK5 would be a therapeutic target for controlling NET-mediated inflammatory disorders.

Original languageEnglish
Pages (from-to)5660-5667
Number of pages8
JournalJournal of Immunology
Volume193
Issue number11
DOIs
Publication statusPublished - Dec 1 2014

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Chemotaxis
Superoxides
Neutrophils
Reactive Oxygen Species
Guanine Nucleotide Exchange Factors
Monomeric GTP-Binding Proteins
Extracellular Traps
Autoimmunity
Innate Immunity
Integrins
Blood Vessels
Leukocytes
Inflammation
Infection

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation. / Watanabe, Mayuki; Terasawa, Masao; Miyano, Kei; Yanagihara, Toyoshi; Uruno, Takehito; Sanematsu, Fumiyuki; Nishikimi, Akihiko; Côté, Jean François; Sumimoto, Hideki; Fukui, Yoshinori.

In: Journal of Immunology, Vol. 193, No. 11, 01.12.2014, p. 5660-5667.

Research output: Contribution to journalArticle

Watanabe, Mayuki ; Terasawa, Masao ; Miyano, Kei ; Yanagihara, Toyoshi ; Uruno, Takehito ; Sanematsu, Fumiyuki ; Nishikimi, Akihiko ; Côté, Jean François ; Sumimoto, Hideki ; Fukui, Yoshinori. / DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation. In: Journal of Immunology. 2014 ; Vol. 193, No. 11. pp. 5660-5667.
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