Epigenetic upregulation of CXCL12 expression mediates antitubulin chemotherapeutics–induced neuropathic pain

Abstract

Clinically, Microtubule-targeted agents-induced neuropathic pain hampers chemotherapeutics for patients with cancer. Here, we found that application of paclitaxel or vincristine increased the protein and mRNA expression of CXCL12 and frequency and amplitude of miniature excitatory post synaptic currents (mEPSCs) in spinal dorsal horn neurons. Spinal local application of CXCL12 induced the long-term potentiation of nociceptive synaptic transmission and increased the amplitude of mEPSCs. Inhibition of CXCL12 using the transgenic mice (CXCL12) or neutralizing antibody or siRNA ameliorated the mEPSC's enhancement and mechanical allodynia. In addition, paclitaxel and vincristine both could increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the acetylation of histone H4 in the CXCL12-expressing neurons. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that antitubulin chemotherapeutics increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, and contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in CXCL12 gene promoter. Inhibition of STAT3 by intrathecal injection of adeno-associated virus encoding Cre and green fluorescent protein into STAT3 mice or inhibitor S3I-201 into rats suppressed the CXCL12 upsurge by decreasing the acetylation of histone H4. Finally, blockade of CXCR4 but not CXCR7 ameliorated the paclitaxel- or vincristine-induced mechanical allodynia. Together, these results suggested that enhanced interaction between STAT3 and p300 mediated the epigenetic upregulation of CXCL12 in dorsal horn neurons, which contributed to the antitubulin chemotherapeutics-induced persistent pain.

CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model

“…In the SNL model, CCR2 and CXCR2 in the spinal neurons may change neuronal properties by activating the ERK signaling, which phosphorylates the NMDA receptor and enhances synaptic transmission . Recently, as a novel regulator of neuropathic pain, CXCL12, was found to be upregulated in the spinal neurons after anti‐tubulin chemotherapeutics in rat . The planter incision model induces CXCL12 upregulation in both neurons and astrocytes .…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…For example, dorsal horn neurons exhibit elevated expression of the chemokine SDF-1α/CXCL12 in a CIPN model [76][77][78], CXCL13 in a rat SNL model [79], and CCL3 and its receptor CCR5 in CCI in rats [80•, 81, 82]. Proinflammatory cytokines such as interferon-γ activate spinal microglia, a process that underlies many of the neuropathy-induced changes in spinal neuron behavior, Lidocaine injection close to the injury of post-surgical neuroma patients [50] Dose-dependent reduction in spontaneous and evoked pain scores by more than 80% Persistent post-herniorrhaphy pain Bupivacaine infiltration of tender points, ultrasound-guided, placebo-controlled Significantly greater analgesia and reduced evoked pain response when compared with placebo Persistent pain after breast cancer surgery (PPBCS) (pilot study)…”

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

“…Overview of possible effects of vincristine on the immune system (Callizot et al, 2008; Kiguchi et al, 2008; Wang et al, 2012; Chatterjee et al, 2014; Old et al, 2014; Makker et al, 2017), peripheral tissues (Old et al, 2014) and sensory neurons (Kaba et al, 1985; Topp et al, 2000; Gan et al, 2010; Areti et al, 2014; Canta et al, 2015; Carozzi et al, 2015; Xu et al, 2017) leading to neuronal inflammation (Chatterjee et al, 2014; Xu et al, 2017) and altered excitability of peripheral neurons (Alessandri-Haber et al, 2008; Old et al, 2014) which may be considered as the main mechanisms contributing to the development of vincristine-induced CIPN. CXCL12, C-X-C Motif Chemokine Ligand 12; CX3CR, C-X-3-C motif chemokine receptor; TNF α, Tumor necrosis factor alpha; ILs, Interleukins; CXCR4, C-X-C motif chemokine receptor 4; ROS, Reactive oxygen species; Na V , Voltage-gated sodium channel; K V , Voltage-gated potassium channel; TRP, Transient receptor potential channel; Ca V , Voltage-gated calcium channel.…”

“…Activation of monocyte-macrophages by the chemokine CX3CL1 also lead to production of ROS and subsequent activation of TRPA1 (Old et al, 2014). Additionally, vincristine and paclitaxel enhanced the binding of the STAT3 (Signal Transducer and Activator of Transcription 3) to the CXCL12 gene promotor (Xu et al, 2017), causing up-regulation of C-X-C Motif Chemokine Ligand 12 in dorsal horn ganglia. CXCL12 is a member of the integrin family and acts as a ligand of the CXCR4 (CD184, C-X-C chemokine receptor type 4) and as an attractant for T-lymphocytes and monocytes.…”