ZFIN ID: ZDB-PUB-130410-36
Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway
Liu, Y.J., Fan, H.B., Jin, Y., Ren, C.G., Jia, X.E., Wang, L., Chen, Y., Dong, M., Zhu, K.Y., Dong, Z.W., Ye, B.X., Zhong, Z., Deng, M., Liu, T.X., and Ren, R.
Date: 2013
Source: The Journal of biological chemistry   288(19): 13551-62 (Journal)
Registered Authors: Chen, Yi, Deng, Min, Dong, Mei, Jin, Yi, Zhu, Kang-Yong
Keywords: cell migration, chemical biology, immunology, signal transduction, zebrafish, CB2, chemical genetic screen, leukocyte migration, Alox5
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Arachidonate 5-Lipoxygenase/genetics
  • Arachidonate 5-Lipoxygenase/metabolism*
  • Base Sequence
  • Cannabinoid Receptor Agonists/pharmacology
  • Cell Movement/drug effects*
  • Gene Expression Regulation, Enzymologic
  • Gene Knockout Techniques
  • Indoles/pharmacology
  • Leukocytes/drug effects
  • Leukocytes/physiology*
  • MAP Kinase Signaling System*
  • Molecular Sequence Data
  • Protein Binding
  • Proto-Oncogene Proteins c-jun/metabolism
  • Receptor, Cannabinoid, CB1/metabolism
  • Receptor, Cannabinoid, CB2/genetics
  • Receptor, Cannabinoid, CB2/metabolism*
  • Tail
  • Time-Lapse Imaging
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 23539630 Full text @ J. Biol. Chem.

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 both 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 Cnr2 agonist and Alox5 inhibitor also provides a potential therapeutic strategy for treating human inflammation-associated diseases.