Potassium channel modulation in macrophages sensitizes dorsal root ganglion neurons after nerve injury

Konnova, Elena A.; Deftu, Alexandru‐Florian; Chu Sin Chung, Paul; Kirschmann, Guylène; Decosterd, Isabelle; Suter, Marc R.

doi:10.1002/glia.24496

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…For instance, the Na + channel subtype Nav1.7 is exclusively expressed in the nociceptive pathways of the PNS and regulates the action potential threshold, which causes an enlarged persistent sodium current associated with SNI‐induced neuropathic pain, STZ‐induced diabetic neuropathic pain, and inflammatory pain. [ 39 , 51 , 52 ] K Ca channels modulate neuronal firing frequency and AHP, generating an outward current that prevents neuronal hyperexcitability. [ 53 , 54 ] However, these channels have not been thoroughly studied in the context of PDNP.…”

Section: Discussionmentioning

confidence: 99%

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Sun,

Yang,

Wang

et al. 2024

Advanced Science

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Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high‐energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two‐pore‐domain K+ channel (K2P) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin‐mediated TREK1/2 pathway may provide a therapeutic approach for ameliorating PDNP.

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Section: Discussionmentioning

confidence: 99%

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Sun,

Yang,

Wang

et al. 2024

Advanced Science

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CTRP9 attenuates peripheral nerve injury-induced mechanical allodynia and thermal hyperalgesia through regulating spinal microglial polarization and neuroinflammation mediated by AdipoR1 in male mice

Liu,

Zhang,

Mei

2024

Cell Biol Toxicol

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Peripheral nerve injury triggers rapid microglial activation, promoting M1 polarization within the spinal cord, which exacerbates the progression of neuropathic pain. C1q/TNF-related protein 9 (CTRP9), an adiponectin homolog, is known to suppress macrophage activation and exhibit anti-inflammatory properties through the activation of adiponectin receptor 1 (AdipoR1) in various disease contexts. Nevertheless, the involvement of CTRP9 in microglial polarization in the context of neuropathic pain is still unclear. Our study aimed to how CTRP9 influences spinal microglial polarization, neuroinflammation, and pain hypersensitivity, as well as the underlying mechanism, using a neuropathic pain model in male mice with spared nerve injury (SNI) of sciatic nerve. Our findings revealed SNI elevated the spinal CTRP9 and AdipoR1 levels in microglia. Furthermore, intrathecal administration of recombinant CTRP9 (rCTRP9) substantially weakened mechanical hypersensitivity and heat-related pain response triggered by SNI. On the other hand, rCTRP9 mediated a phenotypic switch in microglia, from the pro-inflammatory M1 state to the anti-inflammatory M2 state, by influencing the spinal AMPK/NF-κB mechanism in SNI mice. Additionally, treatment with AdipoR1 siRNA or an AMPK-specific antagonist both reversed the effects of CTRP9 on the phenotypic switching of spinal microglia and pain hypersensitivity. Collectively, these results indicate that CTRP9 ameliorates mechanical hypersensitivity and heat-related pain response, shifted the balance of microglia towards the anti-inflammatory M2 state, and suppresses neuroinflammatory responses by modulating the AMPK/NF-κB pathway, mediated by AdipoR1 activation, in mice with SNI. Graphical Abstract

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Dorsal root ganglia CSF1⁺ neuronal subtypes have different impact on macrophages and microglia after spared nerve injury

Grosu,

Gheorghe,

Filippi

et al. 2024

J Peripheral Nervous Sys

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Background and AimsColony‐stimulating factor 1 (CSF1) is a growth factor secreted by dorsal root ganglia (DRG) neurons important for DRG macrophages and spinal cord (SC) microglia injury‐induced proliferation and activation, specifically released after spared nerve injury (SNI). In this study, we investigated if SNI‐induced CSF1 expression and perineuronal rings of macrophages around mouse DRG neurons vary between L3‐L5 DRG and with the neuronal type, and if the CSF1+ neuronal projections at the SC dorsal horns were associated with an increased microglial number in the corresponding laminae.MethodsSeven days after surgery, L3‐L5 DRG as well as their corresponding segments at the SC level were collected, frozen, and cut. DRG sections were double‐immunostained using antibodies against CSF1 and NF200, CGRP or IB4, while SC sections were immunostained using a fluorescent Nissl Stain and analyzed for CX3CR1‐GFP microglia number and distribution by an in‐house ImageJ Plug‐in.ResultsOur results showed that SNI‐induced CSF1 expression was common for all subtypes of mouse DRG neurons, being responsible for attracting more resident macrophages around them in a DRG‐dependent manner, with L4 showing the stronger response and CSF1+/NF200+ neurons showing the highest incidence. Even though the total number of microglia in the SC ipsilateral dorsal horns increased after SNI, the increase at their specific laminar projection sites did not mirror the incidence of DRG neuronal subtypes among CSF1+ neurons.InterpretationTaken together, these results contribute to a more comprehensive understanding of the connection between CSF1 and macrophage/microglia response after SNI and emphasize the importance of considering L3‐L5 DRG individually when investigating SNI‐neuropathic pain pathogenesis in mice.

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Potassium channel modulation in macrophages sensitizes dorsal root ganglion neurons after nerve injury

Cited by 3 publications

References 61 publications

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

CTRP9 attenuates peripheral nerve injury-induced mechanical allodynia and thermal hyperalgesia through regulating spinal microglial polarization and neuroinflammation mediated by AdipoR1 in male mice

Dorsal root ganglia CSF1⁺ neuronal subtypes have different impact on macrophages and microglia after spared nerve injury

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Potassium channel modulation in macrophages sensitizes dorsal root ganglion neurons after nerve injury

Cited by 3 publications

References 61 publications

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

Sortilin‐Mediated Inhibition of TREK1/2 Channels in Primary Sensory Neurons Promotes Prediabetic Neuropathic Pain

CTRP9 attenuates peripheral nerve injury-induced mechanical allodynia and thermal hyperalgesia through regulating spinal microglial polarization and neuroinflammation mediated by AdipoR1 in male mice

Dorsal root ganglia CSF1+ neuronal subtypes have different impact on macrophages and microglia after spared nerve injury

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Dorsal root ganglia CSF1⁺ neuronal subtypes have different impact on macrophages and microglia after spared nerve injury