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Following nerve injury neuregulin‐1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway
Author(s) -
Calvo Margarita,
Zhu Ning,
Grist John,
Ma Zhenzhong,
Loeb Jeffrey A.,
Bennett David L. H.
Publication year - 2011
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.21124
Subject(s) - neuregulin 1 , erbb , microglia , neuregulin , peripheral nerve injury , nerve injury , mapk/erk pathway , neuropathic pain , protein kinase b , biology , signal transduction , neuroscience , microbiology and biotechnology , cancer research , immunology , inflammation , regeneration (biology)
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. © 2011 Wiley‐Liss, Inc.