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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.

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  • Authors+Show Affiliations

    ,

    Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, Graz A-8010, Austria. nariman.balenga@medunigraz.at

    , , , , , , , ,

    Source

    Cell research 21:10 2011 Oct pg 1452-69

    MeSH

    Arachidonic Acids
    Cannabinoid Receptor Modulators
    Cell Degranulation
    Cell Movement
    Endocannabinoids
    Glycerides
    HEK293 Cells
    HL-60 Cells
    Humans
    Inflammation
    Neutrophil Activation
    Neutrophils
    Reactive Oxygen Species
    Receptor, Cannabinoid, CB2
    Receptors, G-Protein-Coupled
    Signal Transduction
    cdc42 GTP-Binding Protein
    rac GTP-Binding Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21467997

    Citation

    TY - JOUR T1 - GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. AU - Balenga,Nariman A B, AU - Aflaki,Elma, AU - Kargl,Julia, AU - Platzer,Wolfgang, AU - Schröder,Ralf, AU - Blättermann,Stefanie, AU - Kostenis,Evi, AU - Brown,Andrew J, AU - Heinemann,Akos, AU - Waldhoer,Maria, Y1 - 2011/04/05/ PY - 2011/4/7/entrez PY - 2011/4/7/pubmed PY - 2012/1/20/medline SP - 1452 EP - 69 JF - Cell research JO - Cell Res. VL - 21 IS - 10 N2 - 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. SN - 1748-7838 UR - https://www.unboundmedicine.com/medline/citation/21467997/abstract/GPR55_regulates_cannabinoid_2_receptor_mediated_responses_in_human_neutrophils_ L2 - http://dx.doi.org/10.1038/cr.2011.60 ER -