Enhanced Repair Effect of Toll-Like Receptor 4 Activation on Neurotmesis: Assessment Using MR Neurography

Li, H. J.; Zhang, Xiang; Zhang, Fujun; Wen, Xuehua; Lu, Liejing; Shen, Jun

doi:10.3174/ajnr.a3977

Cited by 9 publications

(21 citation statements)

References 32 publications

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“…The LPStreated nerves exhibited a better functional recovery at 28 days. These findings are in line with the previous studies, 10,12 where LPS was found to up-regulate TLR4 expression, and then to enhance macrophage recruitment and promote functional recovery.…”

Section: Discussionsupporting

confidence: 93%

“…Toll‐like receptors (TLRs), especially TLR4, are highly expressed in macrophages and Schwann cells, and the TLR signaling pathway plays a critical role in both WD and subsequent functional recovery after PNI . Activation of the TLR4 signaling pathway through lipopolysaccharide (LPS) can promote macrophage recruitment in the injured nerve and accelerate myelin debris clearance, which can lead to better nerve regeneration …”

mentioning

confidence: 99%

“…9 Activation of the TLR4 signaling pathway through lipopolysaccharide (LPS) can promote macrophage recruitment in the injured nerve and accelerate myelin debris clearance, which can lead to better nerve regeneration. [10][11][12] MRI has become a main diagnostic tool to assess the location and extent of nerve injury and to monitor its regenerative process. [13][14][15] Superparamagnetic iron oxide (SPIO) nanoparticle-based contrast agents can be phagocytosed by reticuloendothelial system cells and taken up by monocytes in the circulation after intravenous injection.…”

mentioning

confidence: 99%

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Monitoring of macrophage recruitment enhanced by Toll‐like receptor 4 activation with MR imaging in nerve injury

Chen

Zhang

et al. 2018

Muscle and Nerve

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Monitoring of macrophage recruitment enhanced by Toll‐like receptor 4 activation with MR imaging in nerve injury

Chen

Zhang

et al. 2018

Muscle and Nerve

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“…However, the harsh microenvironment associated with nerve damage or injury is often unfavorable for MSCs to actively repair damaged nerves 21 . The TLR4 signaling pathway activated through local or systemic administration of LPS can enhance macrophage recruitment and accelerate myelin debris clearance to improve the microenvironment, resulting in better nerve recovery in neurotmesis 10,30 . On the other hand, upregulation of inflammatory mediators in the damaged nerve can limit the efficacy of cell‐based therapy 21 .…”

Section: Discussionmentioning

confidence: 99%

“…The rats were housed in a high standard animal facility with free access to food and water. All rats underwent sciatic nerve transection on the left side and received immediate end‐to‐end coaptation, as described elsewhere 10,13,30 . The right sciatic nerve of each animal was explored without transection, which served as the control.…”

Section: Methodsmentioning

confidence: 99%

Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis

et al. 2020

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Introduction:The immuno-microenvironment of injured nerves adversely affects mesenchymal stem cell (MSC) therapy for neurotmesis. Magnetic resonance imaging (MRI) can be used noninvasively to monitor nerve degeneration and regeneration. The aim of this study was to investigate nerve repair after MSC transplantation combined with microenvironment immunomodulation in neurotmesis by using multiparametric MRI.Methods: Rats with sciatic nerve transection and surgical coaptation were treated with MSCs combined with immunomodulation or MSCs alone. Serial multiparametric MRI examinations were performed over an 8-week period after surgery.Results: Nerves treated with MSCs combined with immunomodulation showed better functional recovery, rapid recovery of nerve T2, fractional anisotropy and radial diffusivity values, and more rapid restoration of the fiber tracks than nerves treated with MSCs alone.Discussion: Transplantation of MSCs in combination with immunomodulation can exert a synergistic repair effect on neurotmesis, which can be monitored by multiparametric MRI. K E Y W O R D Simmunomodulation, magnetic resonance imaging, mesenchymal stem cells, peripheral nerve injuries, tacrolimus, toll-like receptors Abbreviations: AD, axial diffusivity; BDNF, brain-derived neurotrophic factor; DTI, diffusion tensor imaging; DTT, diffusion tensor tractography; ELISA, enzyme-linked immunosorbent assay; FA, fractional anisotropy; FKBP, FK-binding protein; GDNF, glial cell-derived neurotrophic factor; GFP, green fluorescent protein; LPS, lipopolysaccharide; MD, mean diffusivity; MRI, magnetic resonance imaging; MSC, mesenchymal stem cell; PBS, phosphate-buffered saline; RD, radial diffusivity; SD, Sprague-Dawley; SFI, sciatic nerve function index; SPRR1A, small proline-rich protein 1A; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α.Zehong Yang and Chushan Zheng contributed equally to this work.

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E6020, a synthetic TLR4 agonist, accelerates myelin debris clearance, Schwann cell infiltration, and remyelination in the rat spinal cord

Church

Milich

Lerch

et al. 2017

Glia

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Oligodendrocyte progenitor cells (OPCs) are present throughout the adult brain and spinal cord and can replace oligodendrocytes lost to injury, aging, or disease. Their differentiation, however, is inhibited by myelin debris, making clearance of this debris an important step for cellular repair following demyelination. In models of peripheral nerve injury, TLR4 activation by lipopolysaccharide (LPS) promotes macrophage phagocytosis of debris. Here we tested whether the novel synthetic TLR4 agonist E6020, a Lipid A mimetic, promotes myelin debris clearance and remyelination in spinal cord white matter following lysolecithin-induced demyelination. In vitro, E6020 induced TLR4-dependent cytokine expression (TNFα, IL1β, IL-6) and NF-κB signaling, albeit at ~10-fold reduced potency compared to LPS. Microinjection of E6020 into the intact rat spinal cord gray/white matter border induced macrophage activation, OPC proliferation, and robust oligodendrogenesis, similar to what we described previously using an intraspinal LPS microinjection model. Finally, a single co-injection of E6020 with lysolecithin into spinal cord white matter increased axon sparing, accelerated myelin debris clearance, enhanced Schwann cell infiltration into demyelinated lesions, and increased the number of remyelinated axons. In vitro assays confirmed that direct stimulation of macrophages by E6020 stimulates myelin phagocytosis. These data implicate TLR4 signaling in promoting repair after CNS demyelination, likely by stimulating phagocytic activity of macrophages, sparing axons, recruiting myelinating cells, and promoting remyelination. This work furthers our understanding of immunemyelin interactions and identifies a novel synthetic TLR4 agonist as a potential therapeutic avenue for white matter demyelinating conditions such as spinal cord injury and multiple sclerosis.

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Enhanced Repair Effect of Toll-Like Receptor 4 Activation on Neurotmesis: Assessment Using MR Neurography

Cited by 9 publications

References 32 publications

Monitoring of macrophage recruitment enhanced by Toll‐like receptor 4 activation with MR imaging in nerve injury

Monitoring of macrophage recruitment enhanced by Toll‐like receptor 4 activation with MR imaging in nerve injury

Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis

E6020, a synthetic TLR4 agonist, accelerates myelin debris clearance, Schwann cell infiltration, and remyelination in the rat spinal cord

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