Volume 21, No 10, Oct 2011

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 21 Issue 10, October 2011: 1452-1469

ORIGINAL ARTICLES

GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils

Nariman A B Balenga¹, Elma Aflaki², Julia Kargl¹, Wolfgang Platzer¹, Ralf Schröder³, Stefanie Blättermann³, Evi Kostenis³, Andrew J Brown⁴, Akos Heinema

¹Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universit鋞splatz 4, Graz A-8010, Austria

²Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

³Section Molecular, Cellular and Pharmacobiology, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany

⁴Department of Screening and Compound Profiling, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK Correspondence: Nariman A B Balenga, Maria Waldhoer,(nariman.balenga@medunigraz.at maria.waldhoer@medunigraz.at)

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 CB₂ receptor (CB₂R), but additional modulatory sites distinct from CB₂R have recently been suggested to impact CB₂R-mediated effector functions in neutrophils. Here, we provide evidence that the recently de-orphanized 7TM/GPCR GPR55 potently modulates CB₂R-mediated responses. We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB₂R 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 CB₂R 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 CB₂R, while it synergizes with CB₂R in recruiting neutrophils to sites of inflammation.

Cell Research (2011) 21:1452-1469. doi:10.1038/cr.2011.60; published online 5 April 2011

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