title: GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.
abstract: The directional migration of neutrophils towards inflammatory mediators, such as chemokines and cannabinoids, occurs via the activation of seven transmembrane G protein coupled receptors (7TM/GPCRs) and is a highly organized process. A crucial role for controlling neutrophil migration has been ascribed to the cannabinoid CB(2) receptor (CB(2)R), but additional modulatory sites distinct from CB(2)R have recently been suggested to impact CB(2)R-mediated effector functions in neutrophils. Here, we provide evidence that the recently de-orphanized 7TM/GPCR GPR55 potently modulates CB(2)R-mediated responses. We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB(2)R agonist 2-arachidonoylglycerol (2-AG), while inhibiting neutrophil degranulation and reactive oxygen species (ROS) production. Using HEK293 and HL60 cell lines, along with primary neutrophils, we show that GPR55 and CB(2)R interfere with each other's signaling pathways at the level of small GTPases, such as Rac2 and Cdc42. This ultimately leads to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils. Therefore, GPR55 limits the tissue-injuring inflammatory responses mediated by CB(2)R, while it synergizes with CB(2)R in recruiting neutrophils to sites of inflammation.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, Graz A-8010, Austria. nariman.balenga@medunigraz.at
authors.forename: Nariman A B
authors.initials: NA
authors.lastname: Balenga
authors.forename: Elma
authors.initials: E
authors.lastname: Aflaki
authors.forename: Julia
authors.initials: J
authors.lastname: Kargl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Platzer
authors.forename: Ralf
authors.initials: R
authors.lastname: Schröder
authors.forename: Stefanie
authors.initials: S
authors.lastname: Blättermann
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Maria
authors.initials: M
authors.lastname: Waldhoer
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C524885:GPR55 protein, human; C094503:glyceryl 2-arachidonate