Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy

J Pain. 2014 Jul;15(7):712-25. doi: 10.1016/j.jpain.2014.04.001. Epub 2014 Apr 19.

Abstract

This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules-myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide-Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy.

Perspective: The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.

Keywords: DRG; LPS-RS; MyD88; Neuropathy; TLR4; TRIF; spinal cord.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / toxicity*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Disease Models, Animal
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Gene Expression Regulation / drug effects
  • Male
  • Myeloid Differentiation Factor 88 / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Paclitaxel / toxicity*
  • Pain Threshold / drug effects
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / genetics*
  • Peripheral Nervous System Diseases / pathology
  • Physical Stimulation
  • Polysaccharides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Time Factors
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Antineoplastic Agents, Phytogenic
  • Myd88 protein, rat
  • Myeloid Differentiation Factor 88
  • Nerve Tissue Proteins
  • Polysaccharides
  • Toll-Like Receptor 4
  • Paclitaxel