The inhibition of Kir2.1 potassium channels depolarizes spinal microglial cells, reduces their proliferation, and attenuates neuropathic pain

Gattlen, Christophe; Deftu, Alexandru‐Florian; Tonello, Raquel; Ling, Yuejuan; Berta, Temugin; Ristoiu, Violeta; Suter, Marc R

doi:10.1002/glia.23831

Cited by 17 publications

(24 citation statements)

References 58 publications

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“…It has been reported that K channel activation and hyperpolarization is critical for microglial motility [33,74]. In addition, spinal microglia reactivity is correlated with K channel activation in neuropathic pain [75,76]. Therefore, these results suggest that membrane hyperpolarization (associated with K channels) instead of depolarization in microglia may activate microglia, likely due to the increase of Ca 2+ driving force.…”

Section: Plos Biologymentioning

confidence: 70%

Optogenetic activation of spinal microglia triggers chronic pain in mice

Liu

Umpierre

et al. 2021

PLoS Biol

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Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been any direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1β production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

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Section: Plos Biologymentioning

confidence: 70%

Optogenetic activation of spinal microglia triggers chronic pain in mice

Liu

Umpierre

et al. 2021

PLoS Biol

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“…Kir2.1 was reported to stabilize the resting V m of many cell types including cardiac myocytes (Sakmann and Trube, 1984), vascular smooth muscle cells (Karkanis et al, 2003;Park et al, 2008;Quayle et al, 1993), endothelial progenitor cells (Quayle et al, 1993;Zhang et al, 2019) and microglial cells (Gattlen et al, 2020). We rst adopted a real-time dynamic detection of peritoneal macrophage V m for 3 min by patch clamp experiments because of a relatively slow inhibitory effect of ML133 on Kir2.1 (Figs.…”

Section: Resultsmentioning

confidence: 99%

An ionic control of metabolic-epigenetic reprogramming links inflammation to membrane potential-mediated nutrient acquisition

Wang¹,

Yu²,

Wang³

et al. 2020

Preprint

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Metabolic and epigenetic reprogramming play pivotal roles in driving inflammation, but the precise regulatory mechanisms remain minimally understood. Here we show an ionic control mediated by macrophage Kir2.1, an inwardly-rectifying K+ channel, promting lipopolysaccharide (LPS)-induced inflammation. Kir2.1 blockade by the selective inhibitor ML133 or its specific deletion in macrophages suppressed the production of LPS-induced inflammatory factors, such as interleukin-1β, and protected mice from LPS-induced sepsis in vivo. Kir2.1 loss-of-function led to a nutrient starvation phenotype, with impaired glucose and serine-glycine-one-carbon metabolism, whose synergy promotes the generation of S-adenosylmethionine (SAM). Accordingly, reduced SAM availability by Kir2.1 blockade decreased histone methylation at key inflammatory effector loci, such as Il1b. Although the immunomodulatory effect of Kir2.1 was independent of modulation by Ca2+ flux and general signaling pathways, its loss-of-function led to a depolarized membrane potential (Vm) which decreased the surface expression of nutrient transporters, including GLUT1 and CD98. We thus identify an ionic control of metabolic- epigenetic reprogramming that links inflammation to Vm-mediated nutrient acquisition and identifies potential new strategies for anti-inflammatory therapy.

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“…It has been reported that K channel activation and hyperpolarization is critical for microglial motility 27,59 . In addition, spinal microglia reactivity is correlated with K channel activation in neuropathic pain 60,61 . Therefore, these results suggest membrane hyperpolarization (associated with K channels) instead of depolarization in microglia may activate microglia, likely due to the increase of Ca 2+ driving force.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic activation of spinal microglia triggers chronic pain in mice

Liu

Umpierre

et al. 2020

Preprint

View full text Add to dashboard Cite

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in neuropathic pain. However, there has not been any direct evidence showing selective microglial activation in vivo is sufficient to induce chronic pain. Here we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity lasting for 5-7 days. In addition, activation of microglial ReaChR upregulated neuronal c-fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased IL-1β production. IL-1 receptor antagonist was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

show abstract

The inhibition of Kir2.1 potassium channels depolarizes spinal microglial cells, reduces their proliferation, and attenuates neuropathic pain

Cited by 17 publications

References 58 publications

Optogenetic activation of spinal microglia triggers chronic pain in mice

Optogenetic activation of spinal microglia triggers chronic pain in mice

An ionic control of metabolic-epigenetic reprogramming links inflammation to membrane potential-mediated nutrient acquisition

Optogenetic activation of spinal microglia triggers chronic pain in mice

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