Cannabinoid Receptor 2 Suppresses Leukocyte Inflammatory Migration by Modulating the JNK/c-Jun/Alox5 Pathway

• DOI: 10.1074/jbc.m113.453811
• Publication Date: 2013-03-29T00:54:20Z
• Authors: Yi-Jie Liu; Hong-Bo Fan; Yi Jin; Chun-Guang Ren; Xiao-E Jia; Lei Wang; Yi Chen; Mei Dong; Kang-Yong Zhu; Zhi-Wei Dong; Bai-Xin Ye; Zhong Zhong; Min Deng; Ting Xi Liu; Ruibao Ren
• Keywords: Cannabinoid Receptor Agonists; Tail; 0301 basic medicine; 0303 health sciences; Arachidonate 5-Lipoxygenase; Indoles; Base Sequence; MAP Kinase Signaling System; Proto-Oncogene Proteins c-jun; Molecular Sequence Data; Zebrafish Proteins; Time-Lapse Imaging; Gene Expression Regulation, Enzymologic; 3. Good health; Animals, Genetically Modified; Receptor, Cannabinoid, CB2; Gene Knockout Techniques; 03 medical and health sciences; Receptor, Cannabinoid, CB1; Cell Movement; Leukocytes; Animals; Zebrafish; Protein Binding

The role of cannabinoid receptor type 2 (Cnr2) in regulating immune function had been widely investigated, but the mechanism is not fully understood.Cnr2 activation down-regulates 5-lipoxygenase (Alox5) expression by suppressing the JNK/c-Jun activation.The Cnr2-JNK-Alox5 axis modulates leukocyte inflammatory migration.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.