Toll-Like Receptor 4 Signaling Contributes to Paclitaxel-Induced Peripheral Neuropathy

Abstract

This paper tests the contribution of the toll-like receptors (TLRs), TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). TLR4 and its immediate down-stream signaling molecules MyD88 and TRIF were increased in dorsal root ganglion (DRG) by western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88 was blocked by co-treatment with the TLR4 antagonist LPS-RS 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 two weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both CGRP- and IB4-positive small DRG neurons. MyD88 was only found in CGRP-positive neurons and TRIF was found both in CGRP- and IB4-positive small DRG neurons as well as in medium and large size DRG neurons. In spinal cord TLR4 was only found co-localized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-RS (LPS-RS) transiently reversed pre-established CIPN mechanical hypersensitivity. These results strongly implicate TLR4 signaling in DRG and spinal cord in the induction and maintenance of paclitaxel related CIPN.

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

“…The doses of PDTC and SN50 used in this study were based on a previous study [11] . The LPS-RS was diluted in PBS to a fi nal concentration of 2 μg/μL, as in a previous report [25] .…”

The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4

“…Another member of this family, TLR4, plays a key role in the transition of inflammatory pain to chronic status and in promoting the generation of nerve injury pain (Christianson et al, 2011;Agalave et al, 2014). More recently, the expression and signaling of TLR4 was shown to be increased with paclitaxel treatment and cotreatment of rats with a TLR4 antagonist during chemotherapy prevented the development of the CIPN phenotype (Li et al, 2014b). Paclitaxel appears to engage TLR4 in the same fashion as its canonical, well known proinflammatory agonist lipopolysaccharide (LPS) (Han et al, 1994;Karin and Ben-Neriah, 2000;Byrd-Leifer et al, 2001;Byrd-Leifer et al, 2001;Li et al, 2013), resulting in the induction and release of the same proinflammatory cytokines from macrophages and other cells (O'Brien et al, 1995;Zaks-Zilberman et al, 2001).…”

Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter

“…Our organs are heavily innervated by the peripheral nerves, yet, it is not fully understood how the PNS controls immunity [2]. Toll-like receptors (TLRs) are traditionally expressed in immune cells to regulate innate immunity, but recent studies indicated that TLRs (such as TLR3, 4 and 7) are also expressed in primary sensory neurons, especially nociceptive neurons in dorsal root ganglia (DRGs) and trigeminal ganglia of the PNS to regulate sensory functions such as pain and itch [3][4][5][6]. TLR signaling is largely mediated by the myeloid differentiation factor 88 (MyD88) protein (but see [7]), and activation of MyD88 in turn activates the NF-κB and MAP kinase pathways, leading to the production of inflammatory cytokines and chemokines for the initiation of innate immunity [3].…”

“…Chemotherapy is known to cause peripheral nerve neuropathy and neuropathic pain [5]. Unlike other neuropathic pain models which only affect limited numbers of DRGs of an animal, chemotherapy drugs, such as paclitaxel (PTX) could affect all DRGs following systemic injection.…”

“…MyD88 was shown to regulate neuropathic pain after chemotherapy [5]. However, the distinct role of MyD88 in neurons vs non-neuronal cells in chronic pain has not been clearly defined.…”