Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway
- Authors
- 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.
- ID
- ZDB-PUB-130410-36
- 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
-
- Tail
- Animals, Genetically Modified
- Molecular Sequence Data
- MAP Kinase Signaling System*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Gene Expression Regulation, Enzymologic
- Receptor, Cannabinoid, CB2/genetics
- Receptor, Cannabinoid, CB2/metabolism*
- Gene Knockout Techniques
- Cell Movement/drug effects*
- Zebrafish
- Leukocytes/drug effects
- Leukocytes/physiology*
- Proto-Oncogene Proteins c-jun/metabolism
- Protein Binding
- Cannabinoid Receptor Agonists/pharmacology
- Animals
- Time-Lapse Imaging
- Arachidonate 5-Lipoxygenase/genetics
- Arachidonate 5-Lipoxygenase/metabolism*
- Indoles/pharmacology
- Receptor, Cannabinoid, CB1/metabolism
- Base Sequence
- PubMed
- 23539630 Full text @ J. Biol. Chem.
- CTD
- 23539630
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.