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The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy

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Tanga, Flobert Y., Nutile-McMenemy, Nancy, DeLeo, Joyce A.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0501634102PMC PMC556308
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Abstract

Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and point-mutant) mice after L5 nerve transection. In a complementary study, TLR4 antisense oligodeoxynucleotide (ODN) was administered intrathecally to L5 spinal nerve injured rats to reduce the expression of spinal TLR4. Both the genetically altered mice and the rats treated with TLR4 antisense ODN displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines as compared with their respective control groups. This finding shows that TLR4 contributes to the initiation of CNS neuroimmune activation after L5 nerve transection. Further understanding of this early, specific, innate CNS/microglial response and how it leads to sustained glial/neuronal hypersensitivity may point to new therapies for the prevention and treatment of neuropathic pain syndromes.

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Authors
Tanga, F. Y., Nutile-McMenemy, N., & DeLeo, J. A.
Affiliations
  • Dartmouth–Hitchcock Medical Center (US)
  • Departments of Anesthesiology and Pharmacology and Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, NH 03756
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-04-04
Volume
102
Issue
16
Pages
5856-5861
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0501634102
PMC
PMC556308
OpenAlex
W2036436547
Cited by
634
References
46
Citations by year
2026: 15 · 2025: 8 · 2024: 19 · 2023: 15 · 2022: 19 · 2021: 25 · 2020: 38 · 2019: 30 · 2018: 38 · 2017: 26 · 2016: 25 · 2015: 41 · 2014: 27 · 2013: 45 · 2012: 44
FWCI
20.37
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Drug Abuse (DA 11276, R01DA011276)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
TLR4, neuropathic pain, microglia, spinal nerve transection, behavioral hypersensitivity, inflammatory cytokines, TLR4 knockout mice, antisense oligodeoxynucleotides, intrathecal administration, glial activation
MeSH terms
Animals, Behavior, Animal, Central Nervous System, Dose-Response Relationship, Drug, Immunity, Innate, Injections, Spinal, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Oligodeoxyribonucleotides, Pain, Receptors, Immunologic, Spinal Nerves, Neuroimmunomodulation, Cytokines, Rats, Sprague-Dawley, Microglia, Toll-Like Receptor 4, Mice, Rats

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