title: Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway.
abstract: BACKGROUND
  The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood.
  
  
  RESULTS
  Cnr2 activation down-regulates 5-lipoxygenase (Alox5) expression by suppressing the JNK/c-Jun activation.
  
  
  CONCLUSIONS
  The Cnr2-JNK-Alox5 axis modulates leukocyte inflammatory migration.
  
  
  CONCLUSIONS
  Linking two important regulators in leukocyte inflammatory migration and providing a potential therapeutic strategy for treating human inflammation-associated diseases. Inflammatory migration of immune cells is involved in many human diseases. Identification of molecular pathways and modulators controlling inflammatory migration could lead to therapeutic strategies for treating human inflammation-associated diseases. The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood. Through a chemical genetic screen using a zebrafish model for leukocyte migration, we found that both an agonist of the Cnr2 and inhibitor of the 5-lipoxygenase (Alox5, encoded by alox5) inhibit leukocyte migration in response to acute injury. These agents have a similar effect on migration of human myeloid cells. Consistent with these results, we found that inactivation of Cnr2 by zinc finger nuclease-mediated mutagenesis enhances leukocyte migration, while inactivation of Alox5 blocks leukocyte migration. Further investigation indicates that there is a signaling link between Cnr2 and Alox5 and that alox5 is a target of c-Jun. Cnr2 activation down-regulates alox5 expression by suppressing the JNK/c-Jun activation. These studies demonstrate that Cnr2, JNK, and Alox5 constitute a pathway regulating leukocyte migration. The cooperative effect between the Cnr2 agonist and Alox5 inhibitor also provides a potential therapeutic strategy for treating human inflammation-associated diseases.
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yi-Jie
authors.initials: YJ
authors.lastname: Liu
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Fan
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Chun-Guang
authors.initials: CG
authors.lastname: Ren
authors.forename: Xiao-E
authors.initials: XE
authors.lastname: Jia
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Kang-Yong
authors.initials: KY
authors.lastname: Zhu
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Dong
authors.forename: Bai-Xin
authors.initials: BX
authors.lastname: Ye
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhong
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.forename: Ting Xi
authors.initials: TX
authors.lastname: Liu
authors.forename: Ruibao
authors.initials: R
authors.lastname: Ren
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D007211:Indoles / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D013623:Tail; D059008:Time-Lapse Imaging; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; C518179:Cnr2 protein, zebrafish; D007211:Indoles; D016755:Proto-Oncogene Proteins c-jun; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D029961:Zebrafish Proteins; D001094:Arachidonate 5-Lipoxygenase; C402944:JHW 015
keywords: Alox5; CB2; Cell Migration; Chemical Biology; Chemical Genetic Screen; Immunology; Leukocyte Migration; Signal Transduction; Zebra Fish
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