ArticlePain2014
TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling.
Article in Pain, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 145 citations in OpenAlex.
- Glial cells in neuropathic pain.Physiological reviews · 2026Review
- Analgesic mechanism of Panaphix in spinal nerve-ligated rats: involvement of microglial inflammatory cytokines.Korean journal of anesthesiology · 2026Article
- Article
- Mechanical Compression-Induced Peripheral Neuropathic Pain: From Astrocyte Mechanosensing and Phenotypic Reprogramming to CCL2-CCR2 Axis-Targeted Therapies.Journal of inflammation research · 2026Review
- ER stress-induced ITPR1/ANO1 signaling drives trigeminal neuropathic pain through calcium-dependent neuronal hyperexcitability.The journal of headache and pain · 2025Article
- The Role and Mechanism of TRIM13 Regulation of TRAF6 Ubiquitination in the Synergy of Inflammatory Responses and Neurotoxicity Induced by METH and HIV- 1 Tat Protein in Astrocytes.Neurotoxicity research · 2025Article
- Exploring the early drivers of pain in Parkinson's disease.Scientific reports · 2025Article
- Activation of Bradykinin BInternational journal of molecular sciences · 2024Article
- FTY720/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Effects of Pain Relief Through Minimal Exercise Intervention in a Rat Model of Neuropathic Pain.Cureus · 2024Article
- Cytochrome P450 26A1 Contributes to the Maintenance of Neuropathic Pain.Neuroscience bulletin · 2024Article
- MiR-31-5p regulates the neuroinflammatory response via TRAF6 in neuropathic pain.Biology direct · 2024Article
- Identification and validation of aging-related genes in neuropathic pain using bioinformatics.Frontiers in genetics · 2024Article
- Harmonizing hope: navigating the osteoarthritis melody through the CCL2/CCR2 axis for innovative therapeutic avenues.Frontiers in immunology · 2024Review
- METTL14 Regulates the m6A Modification of TRAF6 to Suppress Mitochondrial Dysfunction and Ferroptosis in Dopaminergic Neurons via the cGAS-STING Pathway.Current molecular medicine · 2024Article
- Exosomal miR-146a-5p derived from human umbilical cord mesenchymal stem cells can alleviate antiphospholipid antibody-induced trophoblast injury and placental dysfunction by regulating the TRAF6/NF-κB axis.Journal of nanobiotechnology · 2023Article
- Sirtuins: Promising Therapeutic Targets to Treat Ischemic Stroke.Biomolecules · 2023Review
- Kaempferol counteracts bupivacaine-induced neurotoxicity in mouse dorsal root ganglia neurons by regulating TRAF6-dependent NF-κB signaling.The Kaohsiung journal of medical sciences · 2023Article
- Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms.Neuroscience bulletin · 2023Review
- Daphnetin Improves Neuropathic Pain by Inhibiting the Expression of Chemokines and Inflammatory Factors in the Spinal Cord and Interfering with Glial Cell Polarization.Pharmaceuticals (Basel, Switzerland) · 2023Article
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The proinflammatory cytokines tumor necrosis factor (TNF) α and interleukin (IL) 1β have been strongly implicated in the pathogenesis of neuropathic pain, but the intracellular signaling of these cytokines in glial cells is not fully understood. TNF receptor-associated factor 6 (TRAF6) plays a key role in signal transduction in the TNF receptor superfamily and the IL-1 receptor superfamily. In this study, we investigated the role of TRAF6 in neuropathic pain in mice after spinal nerve ligation (SNL). SNL induced persistent TRAF6 upregulation in the spinal cord. Interestingly, TRAF6 was mainly colocalized with the astrocytic marker glial fibrillary acidic protein on SNL day 10 and partially expressed in microglia on SNL day 3. In cultured astrocytes, TRAF6 was upregulated after exposure to TNF-α or IL-1β. TNF-α or IL-1β also increased CCL2 expression, which was suppressed by both siRNA and shRNA targeting TRAF6. TRAF6 siRNA treatment also inhibited the phosphorylation of c-Jun N-terminal kinase (JNK) in astrocytes induced by TNF-α or IL-1β. JNK inhibitor D-NKI-1 dose-dependently decreased IL-1β-induced CCL2 expression. Moreover, spinal injection of TRAF6 siRNA decreased intrathecal TNF-α- or IL-1β-induced allodynia and hyperalgesia. Spinal TRAF6 inhibition via TRAF6 siRNA, shRNA lentivirus, or antisense oligodeoxynucleotides partially reversed SNL-induced neuropathic pain and spinal CCL2 expression. Finally, intrathecal injection of TNF-α-activated astrocytes induced mechanical allodynia, which was attenuated by pretreatment of astrocytes with TRAF6 siRNA. Taken together, the results suggest that TRAF6, upregulated in spinal cord astrocytes in the late phase after nerve injury, maintains neuropathic pain by integrating TNF-α and IL-1β signaling and activating the JNK/CCL2 pathway in astrocytes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.