Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain
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ABSTRACT:
PROVIDER: PRJNA647814 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12279200_1.fastq.gz | Fastqsanger.gz | |||
| SRR12279200_2.fastq.gz | Fastqsanger.gz | |||
| SRR12279201_1.fastq.gz | Fastqsanger.gz | |||
| SRR12279201_2.fastq.gz | Fastqsanger.gz | |||
| SRR12279202_1.fastq.gz | Fastqsanger.gz |
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Project description:Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naïve mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia nor reversed CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
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| S-EPMC8111462 | biostudies-literature
Project description:Objective: Chronic pain is a major problem in patients with spinal cord injury (SCI). According to different studies, approximately 70% of patients with SCI experience persistent pain. Although previous gene expression profiling studies have been conducted in animal models, gene expression profiling study in human whole blood has not been reported yet. The objective of this study was to define the gene expression profile of neuropathic pain in spinal cord injured patients. Materials and Methods: We performed gene expression analysis including 20.000 genes using Affymetrix GeneChip® Primeview™ Human Gene Expression Arrays. For confirmation of expression levels of selected genes, we performed real time polymerase chain reaction. We gathered samples from periferic blood mononuclear cells. Data of twelve patients with intractable neuropathic pain was compared with thirteen patients who don’t have pain. All patients have complete injuries with a level of injury above T5. Results: A total of 16 differentially expressed genes including 9 up-regulated and 7 down-regulated were obtained with a cut-off degree at 4 fold change. EIF1AY, RPS4Y1, DDX3Y, RPL31, ETS1, KLF3, JUN, CYorf15B, and ERAP2 were in up-regulated and HLA-C, XIST, C4BPA, FAM118A, ZNF506, OVOS2, and C1D were in down-regulated group. KEGG pathway database showed that 14.6% of genes were enriched in the nodes of immune system. Real time polymerase chain reaction analyses did not increase to statistically significant levels for confirmation of gene expression analyze results. Conclusions: Considering these data, findings of this first gene expression study in humans with SCI might provide valuable information for future targets for understanding neuropathic pain pathogenesis. The results of gene expression analyses were not confirmed by real time polymerase chain reaction. Studies with larger sample size are needed for confirmation. This is a cross-sectional study with a control group. Patients were divided into two groups according to intractable neuropathic pain existence.There were 12 patients in group A (Patients with pain) and 13 patients in control group.
2015-06-16 | E-GEOD-69901 | biostudies-arrayexpress
Project description:Astrocytes in the spinal cord dorsal horn (SDH) play a pivotal role in synaptic transmission and neuropathic pain. However, the precise classification of SDH astrocytes in health and disease remains elusive. Here we reveal Gpr37l1 as a marker and functional regulator of spinal astrocytes. Through single-nucleus RNA sequencing, we identified Gpr37l1 as a selective GPCR marker for spinal cord astrocytes. Notably, SDH displayed reactive astrocyte phenotypes and exacerbated neuropathic pain following nerve injury combined with Gpr37l1 deficiency. In naïve animals, GPR37L1 knockdown in SDH astrocytes induces astrogliosis and pain hypersensitivity, while Gpr37l1-/- mice fail to recover from neuropathic pain. GPR37L1 activation by maresin-1 increased astrocyte GLT-1 activity and reduced spinal EPSCs and neuropathic pain. Selective overexpression of Gpr37l1 in SDH astrocytes reversed neuropathic pain and astrogliosis after nerve injury. Our findings illuminate astrocyte GPR37l1 as an essential negative regulator of pain, which protects neuropathic pain through astrocyte signaling in SDH.
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Project description:This program addresses the gene signature associated with DRG in the Chung rat model for neuropathic pain. The Chung neuropathic pain profiling data was analyzed by identifying genes that were up- and down-regulated at selected p value and fold change in DRG of the Sprague Dawley rats following spinal nerve ligation compared to the sham-operated controls.
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Project description:Chronic pain arises from an imbalance between excitation and inhibition. For chronic pain caused by peripheral nerve injury, sensory neuron damage leads to changes in spinal pain transduction, where enhanced excitatory and/or loss of inhibitory pathways can drive pain diseases. At the cellular level, the transcriptional changes occurring in entrenched chronic pain are largely unknown. Here we use single nuclei and spatial transcriptomic approaches to investigate the cellular and molecular causes of entrenched and treated neuropathic pain. Our data show that nerve injury leads to broad upregulation of spinal synaptic and excitatory pathways in dorsal neuronal and glial populations. We confirm these core populations are conserved in the human spinal cord, and show an effective pain therapy acts by dampening these neuropathic transcriptional programs. Overall, our data provides the first high resolution transcriptional analysis of the neuropathic spinal cord, highlighting known and novel pathways that may help us better manage pain diseases.
2026-04-28 | GSE328700 | GEO
Project description:Chronic pain arises from an imbalance between excitation and inhibition. For chronic pain caused by peripheral nerve injury, sensory neuron damage leads to changes in spinal pain transduction, where enhanced excitatory and/or loss of inhibitory pathways can drive pain diseases. At the cellular level, the transcriptional changes occurring in entrenched chronic pain are largely unknown. Here we use single nuclei and spatial transcriptomic approaches to investigate the cellular and molecular causes of entrenched and treated neuropathic pain. Our data show that nerve injury leads to broad upregulation of spinal synaptic and excitatory pathways in dorsal neuronal and glial populations. We confirm these core populations are conserved in the human spinal cord, and show an effective pain therapy acts by dampening these neuropathic transcriptional programs. Overall, our data provides the first high resolution transcriptional analysis of the neuropathic spinal cord, highlighting known and novel pathways that may help us better manage pain diseases.
2026-04-28 | GSE325938 | GEO
Project description:We produced single-cell transcriptomes from the mouse spinal cord using Drop-seq in animals modeling neuropathic pain and superficial injury (SI) controls. We used the spared nerve injury (SNI) model of neuropathic pain. ~10,000 cells from sham surgery controls and ~9,000 cells from SNI animals were sequenced. Unbiased cell clustering yielded 66 spinal cell subtypes sequenced at relatively low depth (~1200 transcripts/cell). Comparisons between SI and SNI cells were performed to investigate cell-specific differences during a neuropathic pain state.
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Project description:Chronic pain arises from an imbalance between excitation and inhibition. For chronic pain caused by peripheral nerve injury, sensory neuron damage leads to changes in spinal pain transduction, where enhanced excitatory and/or loss of inhibitory pathways can drive pain diseases. At the cellular level, the transcriptional changes occurring in entrenched chronic pain are largely unknown. Here we use single nuclei and spatial transcriptomic approaches to investigate the cellular and molecular causes of entrenched and treated neuropathic pain. Our data show that nerve injury leads to broad upregulation of spinal synaptic and excitatory pathways in dorsal neuronal and glial populations. We confirm these core populations are conserved in the human spinal cord, and show an effective pain therapy acts by dampening these neuropathic transcriptional programs. Overall, our data provides the first high resolution transcriptional analysis of the neuropathic spinal cord, highlighting known and novel pathways that may help us better manage pain diseases.
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