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. © 2011 Wiley-Liss, Inc.

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats

“…Recently, MAPK/ERK, PI3K/Akt, and JAK/STAT3 signaling pathways that regulate naturally-occurring cell proliferation have been identified following nerve injury in mammals [74,75]. In spinal cord injury models, neuregulin-1-erbB activating microglial proliferation was dependent on the MAPK/ERK pathway [76]. Zuo et al found that gastrodin effectively promoted proliferation and migration of RSC96cells by regulating gene expression of PI3K/Akt and ERK1/2 phosphorylation [77].…”

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

“…Given the proximity of ErbB2 to AChRs, we next examined whether neuregulin-1 acts through ErbB2 to potentiate n-agrin-induced AChR clustering. To address this, we used the ErbB2 inhibitor PD168393 (Calvo et al, 2011). C2C12 myotubes were cultured with 1 nM n-agrin in the presence or absence of 3 nM neuregulin-1, and each of these were tested in the presence or absence of 10 mM PD168393 (Fig.…”

“…NSC-87877, a Shp2 inhibitor (Chen et al, 2006) was obtained from Merck (Zhao et al, 2007). PD168393 was purchased from Merck and used to inhibit ErbB2 (Calvo et al, 2011). Tetramethylrhodamine isothiocyanate (TRITC)-conjugated a-bungarotoxin (TRITC-a-BTX; Sigma, St. Louis, MO) was used at 1:10,000 in differentiation medium.…”

Cetuximab alleviates neuropathic pain despite tumour progression

“…Communication between the involved cells is complex and depends partly on signalling via the family of mitogen-activated protein kinase (MAPK) proteins which have been proposed as targets for therapies directed against NP, as well as other chronic neurological diseases 9–12. Several small molecules designed to inhibit the intracellular MAPK-signalling pathway are currently undergoing clinical phase I and II studies 13.…”