Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury.
A key component in the response of the nervous system to injury is the proliferation and switch to a "proinflammatory" phenotype by microglia (microgliosis). In situations where the blood-brain barrier is intact, microglial numbers increase via the proliferation and chemotaxis of resident microglia; however, there is limited knowledge regarding the factors mediating this response. After peripheral nerve injury, a dorsal horn microgliosis develops, which directly contributes to the development of neuropathic pain. Neuregulin-1 (NRG-1) is a growth and differentiation factor with a well characterized role in neural and cardiac development. Microglia express the NRG1 receptors erbB2, 3, and 4, and NRG1 signaling via the erbB2 receptor stimulated microglial proliferation, chemotaxis, and survival, as well as interleukin-1beta release in vitro. Intrathecal treatment with NRG1 resulted in microglial proliferation within the dorsal horn, and these cells developed an activated morphology. This microglial response was associated with the development of both mechanical and cold pain-related hypersensitivity. Primary afferents express NRG1, and after spinal nerve ligation (SNL) we observed both an increase in NRG1 within the dorsal horn as well as activation of erbB2 specifically within microglia. Blockade of the erbB2 receptor or sequestration of endogenous NRG after SNL reduced the proliferation, the number of microglia with an activated morphology, and the expression of phospho-P38 by microglia. Furthermore, consequent to such changes, the mechanical pain-related hypersensitivity and cold allodynia were reduced. NRG1-erbB signaling therefore represents a novel pathway regulating the injury response of microglia.
Calvo
Margarita
M
Wolfson Center for Age Related Diseases, King's College London, London SE1 1UL, United Kingdom.
Zhu
Ning
N
Tsantoulas
Christoforos
C
Ma
Zhenzhong
Z
Grist
John
J
Loeb
Jeffrey A
JA
Bennett
David L H
DL
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D005911:Gliosis / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D017628:Microglia / Q000502:physiology*; D020890:Neuregulin-1 / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013127:Spinal Nerves / Q000293:injuries*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C490580:Nrg1 protein, rat
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