Neuregulin-ErbB Signaling Promotes Microglial Proliferation and Chemotaxis Contributing to Microgliosis and Pain after Peripheral Nerve Injury

Calvo, Margarita; Zhu, Ning; Tsantoulas, Christoforos; Ma, Zhenzhong; Grist, John; Loeb, Jeffrey A.; Bennett, David L.H.

doi:10.1523/jneurosci.5169-09.2010

Cited by 150 publications

(171 citation statements)

References 70 publications

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“…In agreement with this, treatment of chronically denervated nerve explants with recombinant NRG1 type II in the presence of forskolin increased the number of SCs migrating from the explants [97]. Furthermore, cultured peritoneal macrophages express erbB2, erbB3 and, erbB4 and in response to recombinant NRG1 β-EGF domain, show enhanced motility ( Figure 4) [98]. Therefore, in the context of peripheral nerve injury, there is some in vitro evidence that NRG1 signaling may play a role in the migration of both SCs and macrophages.…”

Section: Potential Mechanisms Of Action Of Nrg1 Signaling In Periphersupporting

confidence: 78%

“…Reproduced with permission from [98]. Events after a peripheral nerve injury and the potential roles NRG1 may play in this process (dark boxes) (A-E).…”

Section: Future Perspectivementioning

confidence: 99%

“…(C) Macrophages infiltrate into the distal stump, and within 2 weeks, both macrophages and SCs complete the clearance of debris, and at the same time, dedifferentiated SCs align themselves in bands of Büngner. NRG1 is known to enhance macrophage motility, so it may play a role in macrophage recruitment following nerve injury, although this has not yet been shown in vivo [98]. (D) Axons then regenerate out of the proximal stump following SC tubes and remake contact with SCs.…”

Section: Future Perspectivementioning

confidence: 99%

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The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell. Keywordsneuregulin-1; neuropathy; peripheral nerve injury; regeneration; remyelination; repair; Schwann cell Peripheral nerve injury causes significant morbidity and reduced quality of life as a consequence of weakness, sensory loss and neuropathic pain. In total, 6% of the elderly population suffer from peripheral neuropathy [1], which can be caused by metabolic diseases such as diabetes, inherited genetic disorders such as Charcot-Marie-Tooth disease, infectious and inflammatory disorders including Guillan-Barré syndrome and traumatic injury to the nerve (which alone effects up to 300,000 people in Europe per year [1,2]). In contrast to the CNS, peripheral nerves have a significant regenerative capacity [3]; however, in patients, regeneration and the clinical outcome are often poor. Axons regenerate at a rate of approximately 1 mm per day, depending on the site of the lesion. There may be a delay of months if not years before the target zone is re-innervated, and by this time, the target organ and supporting cells may have irreversibly changed, becoming much less receptive to reinnervation. The current approaches to peripheral nerve repair following nerve transection are either to surgically suture the nerve or to bridge the gap between the two cut ends. Financial & competing interests disclosureThe authors have no other rel evant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Europe PMC Funders Group NRGs & the PNSNRGs Neuregulins are a family of growth factors en...

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Section: Potential Mechanisms Of Action Of Nrg1 Signaling In Periphersupporting

confidence: 78%

“…Reproduced with permission from [98]. Events after a peripheral nerve injury and the potential roles NRG1 may play in this process (dark boxes) (A-E).…”

Section: Future Perspectivementioning

confidence: 99%

Section: Future Perspectivementioning

confidence: 99%

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The Role of Neuregulin-1 In the Response To Nerve Injury

Fricker

Bennett

2011

Future Neurol.

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“…Besides, ATP is actively released from injured primary afferents and dorsal horn neurons, which induce microglial activation after binding to the microglia P2X4 receptor [10]. Another study indicated that SNL induced spinal dorsal horn microgliosis, which directly contributed to the development of neuropathic pain [45]. Microglia expressed the neuregulin 1 receptor (NRG1R), which was a growth and differentiation factor.…”

Section: Discussionmentioning

confidence: 99%

Combination of Tramadol with Minocycline Exerted Synergistic Effects on a Rat Model of Nerve Injury-Induced Neuropathic Pain

et al. 2013

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Neuropathic pain is a refractory clinical problem. Certain drugs, such as tramadol, proved useful for the treatment of neuropathic pain by inhibiting the activity of nociceptive neurons. Moreover, studies indicated that suppression or modulation of glial activation could prevent or reverse neuropathic pain, for example with the microglia inhibitor minocycline. However, few present clinical therapeutics focused on both neuronal and glial participation when treating neuropathic pain. Therefore, the present study hypothesized that combination of tramadol with minocycline as neuronal and glial activation inhibitor may exert some synergistic effects on spinal nerve ligation (SNL)-induced neuropathic pain. Intrathecal tramadol or minocycline relieved SNL-induced mechanical allodynia in a dose-dependent manner. SNL-induced spinal dorsal horn Fos or OX42 expression was downregulated by intrathecal tramadol or minocycline. Combination of tramadol with minocycline exerted powerful and synergistic effects on SNL-induced neuropathic pain also in a dose-dependent manner. Moreover, the drug combination enhanced the suppression effects on SNL-induced spinal dorsal horn Fos and OX42 expression, compared to either drug administered alone. These results indicated that combination of tramadol with minocycline could exert synergistic effects on peripheral nerve injury-induced neuropathic pain; thus, a new strategy for treating neuropathic pain by breaking the interaction between neurons and glia bilaterally was also proposed.

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“…Several growth and differentiation factors also sensitize nociceptors directly, as well as indirectly by allowing neurons to signal microglia and regulate cytokine release and chemotaxis of surrounding cells. These include neuregulin-1, nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 (Polazzi and Contestabile, 2002;Calvo et al, 2010Calvo et al, , 2011. In response to nerve damage, the brain also stimulates the central cytokine cascade, activating further spinal microglia in pain-related areas and causing a positive cycle of cytokine release.…”

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confidence: 99%