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Similarities and differences between the responses induced in human phagocytes through activation of the medium chain fatty acid receptor GPR84 and the short chain fatty acid receptor FFA2R.

Journal article
Authors Martina Sundqvist
Karin Christenson
André Holdfeldt
Michael Gabl
Jonas Mårtensson
Lena Björkman
Regis Dieckmann
Claes Dahlgren
Huamei Forsman
Published in Biochimica et biophysica acta
Volume 1865
Issue 5
Pages 695-708
ISSN 0006-3002
Publication year 2018
Published at Institute of Odontology
Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages 695-708
Language en
Links dx.doi.org/10.1016/j.bbamcr.2018.02...
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords G-protein coupled receptors, Free fatty acids, NADPH-oxidase, Neutrophils, Monocytes
Subject categories Clinical Medicine

Abstract

GPR84 is a recently de-orphanized member of the G-protein coupled receptor (GPCR) family recognizing medium chain fatty acids, and has been suggested to play important roles in inflammation. Due to the lack of potent and selective GPR84 ligands, the basic knowledge related to GPR84 functions is very limited. In this study, we have characterized the GPR84 activation profile and regulation mechanism in human phagocytes, using two recently developed small molecules that specifically target GPR84 agonistically (ZQ16) and antagonistically (GLPG1205), respectively. Compared to our earlier characterization of the short chain fatty acid receptor FFA2R which is functionally expressed in neutrophils but not in monocytes, GPR84 is expressed in both cell types and in monocyte-derived macrophages. In neutrophils, the GPR84 agonist had an activation profile very similar to that of FFA2R. The GPR84-mediated superoxide release was low in naïve cells, but the response could be significantly primed by TNFα and by the actin cytoskeleton disrupting agent Latrunculin A. Similar to that of FFA2R, a desensitization mechanism bypassing the actin cytoskeleton was utilized by GPR84. All ZQ16-mediated cellular responses were sensitive to GLPG1205, confirming the GPR84-dependency. Finally, our data of in vivo transmigrated tissue neutrophils indicate that both GPR84 and FFA2R are involved in neutrophil recruitment processes in vivo. In summary, we show functional similarities but also some important differences between GPR84 and FFA2R in human phagocytes, thus providing some mechanistic insights into GPR84 regulation in blood neutrophils and cells recruited to an aseptic inflammatory site in vivo.

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