Primary Macrophage Chemotaxis Induced by Cannabinoid Receptor 2 Agonists Occurs Independently of the CB2 Receptor

Research output: Contribution to journalArticle

Authors

  • Lewis Taylor
  • Ivy Christou
  • Theodore S Kapellos
  • Alice Buchan
  • Maximillian H Brodermann
  • Matteo Gianella-Borradori
  • Angela Russell
  • David R Greaves

Colleges, School and Institutes

Abstract

Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2(-/-) macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field.

Details

Original languageEnglish
Article number10682
JournalScientific Reports
Volume5
Publication statusPublished - 2 Jun 2015

Keywords

  • Animals, CHO Cells, Cannabinoids, Cell Line, Chemotactic Factors, Chemotaxis, Leukocyte, Cricetulus, Female, Macrophages, Male, Mice, Mice, Knockout, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Receptors, G-Protein-Coupled, Journal Article