title: Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway.
abstract: Following peripheral nerve injury microglia accumulate within the spinal cord and adopt a proinflammatory phenotype a process which contributes to the development of neuropathic pain. We have recently shown that neuregulin-1, a growth factor released following nerve injury, activates erbB 2, 3, and 4 receptors on microglia and stimulates proliferation, survival and chemotaxis of these cells. Here we studied the intracellular signaling pathways downstream of neuregulin-1-erbB activation in microglial cells. We found that neuregulin-1 in vitro induced phosphorylation of ERK1/2 and Akt without activating p38MAPK. Using specific kinase inhibitors we found that the mitogenic effect of neuregulin-1 on microglia was dependant on MEK/ERK1/2 pathway, the chemotactic effect was dependant on PI3K/Akt signaling and survival was dependant on both pathways. Intrathecal treatment with neuregulin-1 was associated with microgliosis and development of mechanical and cold pain related hypersensitivity which was dependant on ERK1/2 phosphorylation in microglia. Spinal nerve ligation results in a robust microgliosis and sustained ERK1/2 phosphorylation within these cells. This pathway is downstream of neuregulin-1/erbB signaling since its blockade resulted in a significant reduction in microglial ERK1/2 phosphorylation. Inhibition of the MEK/ERK1/2 pathway resulted in decreased spinal microgliosis and in reduced mechanical and cold hypersensitivity after peripheral nerve damage. We conclude that neuregulin-1 released after nerve injury activates microglial erbB receptors which consequently stimulates the MEK/ERK1/2 pathway that drives microglial proliferation and contributes to the development of neuropathic pain.
authors.affiliation: Wolfson CARD, Kings College London, Hodgkin Building, Guys Campus, SE1 1UL, London, United Kingdom.
authors.forename: Margarita
authors.initials: M
authors.lastname: Calvo
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Ma
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Loeb
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D020890:Neuregulin-1 / Q000008:administration & dosage / Q000378:metabolism*; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020890:Neuregulin-1; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases