title: The role of G-protein receptor 84 in experimental neuropathic pain.
abstract: G-protein receptor 84 (GPR84) is an orphan receptor that is induced markedly in monocytes/macrophages and microglia during inflammation, but its pathophysiological function is unknown. Here, we investigate the role of GPR84 in a murine model of traumatic nerve injury. Naive GPR84 knock-out (KO) mice exhibited normal behavioral responses to acute noxious stimuli, but subsequent to partial sciatic nerve ligation (PNL), KOs did not develop mechanical or thermal hypersensitivity, in contrast to wild-type (WT) littermates. Nerve injury increased ionized calcium binding adapter molecule 1 (Iba1) and phosphorylated p38 MAPK immunoreactivity in the dorsal horn and Iba1 and cluster of differentiation 45 expression in the sciatic nerve, with no difference between genotypes. PCR array analysis revealed that Gpr84 expression was upregulated in the spinal cord and sciatic nerve of WT mice. In addition, the expression of arginase-1, a marker for anti-inflammatory macrophages, was upregulated in KO sciatic nerve. Based on this evidence, we investigated whether peripheral macrophages behave differently in the absence of GPR84. We found that lipopolysaccharide-stimulated KO macrophages exhibited attenuated expression of several proinflammatory mediators, including IL-1β, IL-6, and TNF-α. Forskolin-stimulated KO macrophages also showed greater cAMP induction, a second messenger associated with immunosuppression. In summary, our results demonstrate that GPR84 is a proinflammatory receptor that contributes to nociceptive signaling via the modulation of macrophages, whereas in its absence the response of these cells to an inflammatory insult is impaired.
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Louise S C
authors.initials: LS
authors.lastname: Nicol
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom, and.
authors.forename: John M
authors.initials: JM
authors.lastname: Dawes
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Federica
authors.initials: F
authors.lastname: La Russa
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Didangelos
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Anna K
authors.identifier: http://orcid.org/0000-0001-7023-066X
authors.initials: AK
authors.lastname: Clark
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.affiliation: GlaxoSmithKline, Harlow, CM19 5AW, United Kingdom.
authors.forename: John B
authors.initials: JB
authors.lastname: Davies
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
authors.affiliation: Wolfson Centre for Age-Related Disease, King's College London, London, SE1 1UL, United Kingdom, stephen.mcmahon@kcl.ac.uk.
authors.forename: Stephen B
authors.identifier: http://orcid.org/0000-0003-4656-5536
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006967:Hypersensitivity / Q000209:etiology / Q000235:genetics; D007249:Inflammation / Q000209:etiology / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation / Q000009:adverse effects; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012585:Sciatica / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; C507114:Gpr84 protein, mouse; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases
keywords: G-protein linked receptors; cytokine; inflammation; macrophage; microglia; neuropathic pain