Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

Richner, Mette; Pallesen, Lone Tjener; Ulrichsen, Maj; Poulsen, Ebbe Toftgaard; Holm, Thomas Hellesøe; Login, Hande; Castonguay, Annie; Lorenzo, Louis‐Etienne; Gonçalves, Nádia Pereira; Andersen, Olav M.; Lykke‐Hartmann, Karin; Enghild, Jan J.; Rønn, Lars Christian B.; Malik, Ibrahim; Bjerrum, Ole J.; Vægter, Christian Bjerggaard; Nykjær, Anders

doi:10.1126/sciadv.aav9946

Cited by 42 publications

(51 citation statements)

References 46 publications

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“…Indeed, macrophage‐neuron interactions have been suggested to be crucial for peripheral sensitization and neuropathic pain (Marchand, Perretti, & McMahon, ; Moalem & Tracey, ; Santa‐Cecília et al, ; Vega‐Avelaira et al, ; Zigmond & Echevarria, ). The timing of this migration is also suggestive: Mice have been shown to develop mechanical allodynia during the first 2–3 days after nerve injury (Richner et al, ; Richner, Bjerrum, Nykjaer, & Vaegter, ), which coincides with the formation of the “ring‐like” structures we report here. We find here that the gene ccl2 encoding the chemokine monocyte chemoattractant protein 1 (MCP1) is upregulated in SGC on Day 3.…”

Section: Discussionsupporting

confidence: 74%

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

Jager

Pallesen

Richner

et al. 2020

Glia

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101

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Satellite glial cells (SGCs) are homeostatic cells enveloping the somata of peripheral sensory and autonomic neurons. A wide variety of neuronal stressors trigger activation of SGCs, contributing to, for example, neuropathic pain through modulation of neuronal activity. However, compared to neurons and other glial cells of the nervous system, SGCs have received modest scientific attention and very little is known about SGC biology, possibly due to the experimental challenges associated with studying them in vivo and in vitro. Utilizing a recently developed method to obtain SGC RNA from dorsal root ganglia (DRG), we took a systematic approach to characterize the SGC transcriptional fingerprint by using next-generation sequencing and, for the first time, obtain an overview of the SGC injury response. Our RNA sequencing data are easily accessible in supporting information in Excel format. They reveal that SGCs are enriched in genes related to the immune system and cell-to-cell communication. Analysis of SGC transcriptional changes in a nerve injury-paradigm reveal a differential response at 3 days versus 14 days postinjury, suggesting dynamic modulation of SGC function over time. Significant downregulation of several genes linked to cholesterol synthesis was observed at both time points. In contrast, regulation of gene clusters linked to the immune system (MHC protein complex and leukocyte migration) was mainly observed after 14 days. Finally, we demonstrate that, after nerve injury, macrophages are in closer physical proximity to both small and large DRG neurons, and that previously reported injury-induced proliferation of SGCs may, in fact, be proliferating macrophages. K E Y W O R D Sdorsal root ganglion, macrophages, nerve injury, nociceptors, pain, peripheral nervous system, satellite glial cells, transcriptome

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Section: Discussionsupporting

confidence: 74%

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

Jager

Pallesen

Richner

et al. 2020

Glia

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101

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“…It is interesting to note that TrkB signaling appears common to both the loss of KCC2 48,50,51,53,54 as well as to the synaptic scaling at GABA A synapses and subunit switch, yet the changes in GABA A R were not secondary to loss of KCC2. We also found that the GABA A R plasticity was Ca 2+ dependent.…”

Section: Discussionmentioning

confidence: 99%

“…The switch in GABA A R subunit composition is BDNFdependent. After PNI, activation of spinal microglial P2X4Rs evokes the release of BDNF 48,49 which is known to down-regulate neuronal KCC2 expression [50][51][52][53][54] . To test whether BDNF was also involved in the GABA A R subunit switch, we incubated slices from control animals for 3 h with BDNF ( Fig.…”

Section: Decrease In Number Of Inhibitory Synapses After Nerve Injurymentioning

confidence: 99%

Enhancing neuronal chloride extrusion rescues α2/α3 GABAA-mediated analgesia in neuropathic pain

et al. 2020

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Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABA A Rs and by an α1-to-α2GABA A R subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABA A R benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Clextrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Clgradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABA A Rsubtypes and restoring Clhomeostasis.

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“…Neuropathic pain is characterized as a hypersensitive response to noxious and innocuous stimuli that results from primary injury or dysfunction of the somatosensory nervous system; it can persist for months to years, even after the primary tissue damage has healed [1]. Neuropathic pain remains as a chronic debilitating condition that affects the quality of life and reduces individual productivity; it is estimated to affect up to 10% of the population [2,3]. The etiology of neuropathic pain is complex and includes diabetic neuropathy, spinal cord injury, post-herpetic neuralgia, demyelinating disease, and cancer.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia

Yang

Deng

et al. 2020

J Neuroinflammation

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Background: Neuroinflammation plays a vital role in the development and maintenance of neuropathic pain. Recent evidence has proved that bone marrow mesenchymal stem cells (BMSCs) can inhibit neuropathic pain and possess potent immunomodulatory and immunosuppressive properties via secreting a variety of bioactive molecules, such as TNF-α-stimulated gene 6 protein (TSG-6). However, it is unknown whether BMSCs exert their analgesic effect against neuropathic pain by secreting TSG-6. Therefore, the present study aimed to evaluate the analgesic effects of TSG-6 released from BMSCs on neuropathic pain induced by chronic constriction injury (CCI) in rats and explored the possible underlying mechanisms in vitro and in vivo. Methods: BMSCs were isolated from rat bone marrow and characterized by flow cytometry and functional differentiation. One day after CCI surgery, about 5 × 10 6 BMSCs were intrathecally injected into spinal cerebrospinal fluid. Behavioral tests, including mechanical allodynia, thermal hyperalgesia, and motor function, were carried out at 1, 3, 5, 7, 14 days after CCI surgery. Spinal cords were processed for immunohistochemical analysis of the microglial marker Iba-1. The mRNA and protein levels of pro-inflammatory cytokines (IL-1β, TNFα, IL-6) were detected by realtime RT-PCR and ELISA. The activation of the TLR2/MyD88/NF-κB signaling pathway was evaluated by Western blot and immunofluorescence staining. The analgesic effect of exogenous recombinant TSG-6 on CCI-induced mechanical allodynia and heat hyperalgesia was observed by behavioral tests. In the in vitro experiments, primary cultured microglia were stimulated with the TLR2 agonist Pam3CSK4, and then co-cultured with BMSCs or recombinant TSG-6. The protein expression of TLR2, MyD88, p-p65 was evaluated by Western blot. The mRNA and protein levels of IL-1β, TNFα, IL-6 were detected by real-time RT-PCR and ELISA. BMSCs were transfected with the TSG-6-specific shRNA and then intrathecally injected into spinal cerebrospinal fluid in vivo or co-cultured with Pam3CSK4-treated primary microglia in vitro to investigate whether TSG-6 participated in the therapeutic effect of BMSCs on CCI-induced neuropathic pain and neuroinflammation.

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Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

Cited by 42 publications

References 46 publications

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

Enhancing neuronal chloride extrusion rescues α2/α3 GABAA-mediated analgesia in neuropathic pain

Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia

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