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.
Key words
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Article info
Publication history
Published online: April 21, 2014
Accepted:
April 5,
2014
Received in revised form:
March 12,
2014
Received:
November 26,
2013
Footnotes
Supported by grants from the National Institutes of Health (NS 046606) and the National Cancer Institute (CA124787).
The authors declare no conflict of interest.
Identification
Copyright
© 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
