The Lipid Receptor G2A (GPR132) Mediates Macrophage Migration in Nerve Injury-Induced Neuropathic Pain

Cells. 2020 Jul 21;9(7):1740. doi: 10.3390/cells9071740.


Nerve injury-induced neuropathic pain is difficult to treat and mechanistically characterized by strong neuroimmune interactions, involving signaling lipids that act via specific G-protein coupled receptors. Here, we investigated the role of the signaling lipid receptor G2A (GPR132) in nerve injury-induced neuropathic pain using the robust spared nerve injury (SNI) mouse model. We found that the concentrations of the G2A agonist 9-HODE (9-Hydroxyoctadecadienoic acid) are strongly increased at the site of nerve injury during neuropathic pain. Moreover, G2A-deficient mice show a strong reduction of mechanical hypersensitivity after nerve injury. This phenotype is accompanied by a massive reduction of invading macrophages and neutrophils in G2A-deficient mice and a strongly reduced release of the proalgesic mediators TNFα, IL-6 and VEGF at the site of injury. Using a global proteome analysis to identify the underlying signaling pathways, we found that G2A activation in macrophages initiates MyD88-PI3K-AKT signaling and transient MMP9 release to trigger cytoskeleton remodeling and migration. We conclude that G2A-deficiency reduces inflammatory responses by decreasing the number of immune cells and the release of proinflammatory cytokines and growth factors at the site of nerve injury. Inhibiting the G2A receptor after nerve injury may reduce immune cell-mediated peripheral sensitization and may thus ameliorate neuropathic pain.

Keywords: 9-HODE; G2A; GPR132; macrophage migration; neuropathic pain; oxidized linoleic acid metabolites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Cycle Proteins / metabolism*
  • Cell Movement*
  • Cytokines / biosynthesis
  • Lipids / chemistry
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Inbred C57BL
  • Nerve Tissue / pathology*
  • Neuralgia / pathology*
  • Nociception
  • Receptors, G-Protein-Coupled / metabolism*
  • Sciatic Nerve / pathology
  • Signal Transduction


  • Cell Cycle Proteins
  • Cytokines
  • G2A receptor
  • Lipids
  • Receptors, G-Protein-Coupled
  • Matrix Metalloproteinase 9