title: DOCK2 and DOCK5 act additively in neutrophils to regulate chemotaxis, superoxide production, and extracellular trap formation.
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.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Mayuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Masao
authors.initials: M
authors.lastname: Terasawa
authors.affiliation: Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Kei
authors.initials: K
authors.lastname: Miyano
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Yanagihara
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Takehito
authors.initials: T
authors.lastname: Uruno
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, Sagamihara 252-0373, Japan;
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.affiliation: Institut de Recherches Cliniques de Montréal, Université de Montréal, Montreal, Quebec H2W 1R7, Canada; and.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.affiliation: Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan fukui@bioreg.kyushu-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics; D065206:Extracellular Traps / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C574221:4-(3'-(2'-chlorophenyl)-2'-propen-1'-ylidene)-1-phenyl-3,5-pyrazolidinedione; C471356:DOCK2 protein, mouse; C531318:Dock5 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013481:Superoxides; D020744:rac GTP-Binding Proteins