Role of myelin-derived antigens in pain: a female connection
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PROVIDER: PRJNA419179 | ENA |
REPOSITORIES: ENA
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Project description:Intrasciatic injections of the MBP84-104-WT (wild type) peptide, MBP84-104-SCR (scramble) peptide and PBS carrier were conducted in female and male mice (n=6). In 7 days after the intrasciatic injection the specimens of sciatic nerves (SN), dorsal root ganglia (DRG) and dorsal spinal cord (DSC) were collected and the RNA-seq was conducted.
2020-06-12 | GSE107159 | GEO
Project description:An insulating myelin sheath ensures saltatory conduction of mechanosensory A afferents. Myelin damage results in the electrical instability of A fibers and the ability to generate pain in response to light touch/pressure (mechanical allodynia). We have hypothesized and then established that the release of T cell epitopes of myelin basic protein (MBP) enables nociceptive circuitry in myelinated fibers. Thus, mass spectrometry analysis of the rat sciatic nerve proteome followed by bioinformatics examination of the datasets revealed a loss of MBP and activation of T-helper cell signaling in the nerves undergoing chronic constriction injury (CCI). Matrix metalloproteinase-9 (MMP-9) proteolysis resulted in the MBP digest peptides, including the MBP84-104 and MBP68-86 regions, which exhibit prominent immunogenic epitopes. Myelin-forming Schwann cells and paranodal areas accumulated MHCII, MMP-9 and the degraded MBP at the sciatic nerve injury site. Administration of the immunodominant MBP84-104 and MBP68-86 peptides but not of the control peptides in a naïve rat sciatic nerve produced robust mechanical allodynia. Allodynia was accompanied by the T cell infiltration and an increase in MHCII, IL-17A and TNF- levels at the nerve injection site and the segmental ganglia. The pro-nociceptive activity of the synthetic MBP84-104 diminished in athymic nude rats lacking T cells. SB-3CT, an antagonist of MMP-9, inhibited mechanical allodynia, neuroinflammation and spinal sensitization after CCI. Collectively, our novel data implicate, for the first time, MMP-mediated cleavage of MBP and the resulting MBP digest fragments as a major cause of neuropathic pain. Gene extression profiling of total RNAs extracted from rat sciatic nerves, dorsal root ganglion and spinal cords after MBP84-104 peptide injection
2012-03-03 | E-GEOD-34868 | biostudies-arrayexpress
Project description:Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces long-term structural, functional and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the similarity and differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results show that the SNI-induced transcriptomic changes in female and male mice are largely distinct. Interestingly, the female mice exhibit more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurs in the mPFC. Cell type enrichment analyses reveal that the differentially expressed genes involve genes enriched in both neurons and various types of glia. We further performed Gene Set Enrichment Analysis (GSEA), which reveal significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization and mitochondria function are enriched, and gene sets for extracellular matrix are de-enriched after SNI, while such signatures are absent in male ACC. Collectively, these findings reveal sexual dimorphism at the transcriptional level induced by neuropathic pain, and provide novel therapeutic targets for chronic pain and its associated affective disorders.
2022-04-03 | GSE197233 | GEO
Project description:An insulating myelin sheath ensures saltatory conduction of mechanosensory A afferents. Myelin damage results in the electrical instability of A fibers and the ability to generate pain in response to light touch/pressure (mechanical allodynia). We have hypothesized and then established that the release of T cell epitopes of myelin basic protein (MBP) enables nociceptive circuitry in myelinated fibers. Thus, mass spectrometry analysis of the rat sciatic nerve proteome followed by bioinformatics examination of the datasets revealed a loss of MBP and activation of T-helper cell signaling in the nerves undergoing chronic constriction injury (CCI). Matrix metalloproteinase-9 (MMP-9) proteolysis resulted in the MBP digest peptides, including the MBP84-104 and MBP68-86 regions, which exhibit prominent immunogenic epitopes. Myelin-forming Schwann cells and paranodal areas accumulated MHCII, MMP-9 and the degraded MBP at the sciatic nerve injury site. Administration of the immunodominant MBP84-104 and MBP68-86 peptides but not of the control peptides in a naïve rat sciatic nerve produced robust mechanical allodynia. Allodynia was accompanied by the T cell infiltration and an increase in MHCII, IL-17A and TNF- levels at the nerve injection site and the segmental ganglia. The pro-nociceptive activity of the synthetic MBP84-104 diminished in athymic nude rats lacking T cells. SB-3CT, an antagonist of MMP-9, inhibited mechanical allodynia, neuroinflammation and spinal sensitization after CCI. Collectively, our novel data implicate, for the first time, MMP-mediated cleavage of MBP and the resulting MBP digest fragments as a major cause of neuropathic pain.
2012-03-03 | GSE34868 | GEO
Project description:We demonstrated the pain-specific response to the algesic peptide fragment MBP84-104 of myelin basic protein that induces pain if injected into sciatic nerve of rats and mice. We used the wild-type peptide MBP 84-104, H89G mutant peptide (MBP84-104-H89G), scramble peptide (MBP84-104-SCR) and phosphomimetic peptide MBP84-104-mimTT to stimulate the primary rat Schwann cell cultures. After 24h we isolated total RNA and conducted genome wide RNA-seq. In addition, we performed RNA-seq using Schwann cells constitutively expressing an MBP84-104-mCherry construct. The gene expression data was analyzed using Ingenuity Pathway Analysis software. We conclude that the Schwann cells expressing MBP84-104 constructs stimulate pain-specific signaling pathways thus representing a relevant model to study neuropathic pain.
2018-08-13 | GSE107020 | GEO
Project description:Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice
| PRJNA766536 | ENA
Project description:Genomics of Pain - Resilience to Pain
| PRJNA498368 | ENA
Project description:Genomics of Pain - Resilience to Pain
| PRJNA498369 | ENA
Project description:Rapid nerve conduction in the CNS is facilitated by the insulation of axons with myelin, a specialized oligodendroglial compartment distant from the cell body. Myelin is turned over and adapted throughout life; however, the molecular and cellular basis of myelin dynamics is not well understood. Hypothesizing that only a fraction of all myelin-related mRNAs has been identified so far, we subjected myelin biochemically purified from mouse brains at various ages to RNA sequencing. We find a surprisingly large pool of transcripts abundant and/or enriched in myelin. Furthermore, a comprehensive analysis showed that the myelin transcriptome is closely related to the myelin proteome but clearly distinct from the transcriptomes of oligodendrocytes and brain tissues, suggesting that the incorporation of mRNAs into the myelin compartment is highly selective. The mRNA-pool in myelin displays maturation-dependent dynamic changes of composition, abundance, and functional associations; however ageing-dependent changes after 6 months of age were minor. We suggest that this transcript pool provides a basis for the local modulation of myelin turnover and adaptation, i.e. in the individual internode. A light-weight membrane fraction enriched for myelin was purified from mouse brains as described previously (Jahn et al., Neuromethods, 2013). For RNA-Seq, RNA was isolated from myelin of mice from indicated ages.
2016-06-24 | E-GEOD-78151 | biostudies-arrayexpress
Project description:Remyelination is a key step in functional nerve regeneration performed by Schwann cells (SC). We have demonstrated that matrix metalloproteinase (MMP)-9 is a major regulator of signal transduction and phenotypic switching in SCs. Herein, genome-wide transcriptional profiling, followed by Ingenuity Pathway Analysis revealed the MMP-9 signaling network and its endogenous inhibitor, TIMP-1, among the top induced genes of the injured sciatic nerve, that co-distributed with MMP-9 in myelinating SCs and the paranodal/nodal areas of myelinated fibers. Homo- and heterodimers of the active and proMMP-9 were purified from injured nerves using gelatin-sepharose. MMP-9 gene deletion increased the number of immature, GFAP+ mSC and post-mitotic cell counts that correlate with shorter myelin internodes in remyelinated fibers lacking MMP-9. MMP-9 is essential to nodal clustering of voltage-gated Na+ (Nav) channels. MMP inhibitor therapy diminished the expression of Nav 1.7 and 1.8. These data established the essential role of MMP-9 in guiding SC differentiation toward myelin production and in molecular assembly of the myelin domains. Modification of Nav channels in myelinated fibers may thus provide an important therapeutic approach for a number of facilitates regeneration and attenuated neuropathic pain. Gene expression profiling of total RNAs extracted from murine sciatic nerves, dorsal root ganglion and spinal cords at day 1 and day 5 post injury.
2012-02-28 | E-GEOD-33454 | biostudies-arrayexpress