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. (2013) Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway. The Journal of biological chemistry. 288(19):13551-62.
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