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-1␤, IL-6, and TNF-␣. 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.

Effect of GPR84 deletion on obesity and diabetes development in mice fed long chain or medium chain fatty acid rich diets

“…More recently the role of GPR84 in other pathologies has been investigated: Nicol et al report a role for GPR84 in response to neuropathic pain [36], while AudoyRémus et al [37] suggest GPR84 deficiency accelerates damage in a murine Alzheimer's disease model. Maddedu et al [38] proposed that GPR84 may have a role in the inflammatory responses of microglia.…”

Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury

“…G-protein-coupled receptor 84 (GPR84) is an orphan receptor that is mainly produced by macrophages during inflammation and upregulated upon sciatic nerve injury [82]. Lack of GPR84 polarizes macrophages toward M2 phenotype and inhibits the development of mechanical or thermal hypersensitivity after sciatic nerve ligation injury [82], suggesting that GPR84 is a negative regulator of macrophage M2 polarization in injured nerves. Taken together, these findings indicate that peripheral nerve injury triggers a microenvironment favoring macrophage M2 polarization via a variety of mechanisms.…”

“…However, the therapeutic application of IL-10 has been limited, CCL2-CCR2 Sciatic nerve ligation injury upregulates the expression of CCL2-CCR2 signal, which in turn polarizes macrophage to M2 phenotype [52,103,112,117,120] GPR84 Ablation of GPR84 induces macrophage M2 polarization after sciatic nerve ligation injury [82] due to the fact that the in vivo bioactive half-life of IL-10 or its peptide fragments only remains for minutes to hours [98]. Interestingly, Potas et al recently found that implantation of IL-10 conjugated electrospun poly(ε-caprolactone) (PCL) nanofibrous scaffolds in sciatic nerve effectively promotes macrophage M2 polarization up to 14 days [90].…”

Complex Pharmacology of Free Fatty Acid Receptors

“…387 Galapogos progressed this chemical into a Phase 2 proof-of-concept study in ulcerative colitis in January 2015; however, the company recently reported (but has not yet published) no clinical improvement in these studies. As Nicol et al have shown that GPR84 knockout mice do not develop mechanical or thermal hypersensitivity subsequent to partial sciatic nerve ligation, 379 it may be interesting to examine the effect of GPR84 antagonists in models of nerve cell injury. 5.1.2.…”