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Published on: October 6, 2022
Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy
Yan Li1, Haijun Zhang1, Hongmei Zhang1
1Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
Unlabelled:
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.
Insights
Toll-like receptor 4 (TLR4) signaling in the dorsal root ganglion and spinal cord contributes to paclitaxel-induced peripheral neuropathy. Targeting TLR4 and MyD88 may offer new treatments for chemotherapy-induced nerve pain.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Paclitaxel chemotherapy can cause peripheral neuropathy, a debilitating side effect.
- Toll-like receptors (TLRs) are involved in immune responses and inflammation.
- The specific role of TLR4 in chemotherapy-induced peripheral neuropathy (CIPN) is not fully understood.
Purpose of the Study:
- To investigate the involvement of toll-like receptor 4 (TLR4) and its downstream signaling molecules in paclitaxel-induced peripheral neuropathy (CIPN).
- To explore potential therapeutic targets for managing CIPN.
Main Methods:
- Western blot analysis to quantify TLR4, MyD88, and TRIF levels in dorsal root ganglion (DRG) and spinal cord.
- Behavioral tests to assess neuropathic pain in response to paclitaxel treatment.
- Administration of TLR4 antagonist (lipopolysaccharide-Rhodobacter sphaeroides) and MyD88 inhibitor peptide.
- Immunohistochemical analysis to localize TLR4, MyD88, and TRIF expression in DRG neurons and spinal cord cells.
Main Results:
- TLR4, MyD88, and TRIF expression increased in the DRG during paclitaxel treatment.
- Blocking TLR4 or MyD88 signaling ameliorated behavioral signs of neuropathy.
- TLR4 was found in specific DRG neuron subtypes and spinal cord astrocytes.
- TLR4 antagonist treatment reversed established mechanical hypersensitivity in CIPN.
Conclusions:
- TLR4 signaling pathway, involving MyD88, plays a critical role in both the initiation and maintenance of paclitaxel-induced peripheral neuropathy.
- The TLR4-MyD88 pathway represents a promising therapeutic target for treating paclitaxel-induced painful neuropathy.
