Electroacupuncture Alleviates Paclitaxel-induced Peripheral Neuropathy by Reducing CCL2-mediated Macrophage Infiltration in Sensory Ganglia and Sciatic Nerve

Abstract Background: Paclitaxel-induced peripheral neuropathy (PIPN) is a common side effect accompanying paclitaxel chemotherapy, resulting in sensory abnormality and neuropathic pain. Conventional medications lack effectiveness on PIPN. Clinical trials identified beneficial effects of acupuncture on PIPN among patients receiving chemotherapy. Here we explored the mechanisms underlying how acupuncture might alleviate PIPN. Methods: A mouse model of PIPN was established by repeated paclitaxel application. Electroacupuncture (EA) was applied at ST36 and BL60 acupoints of model mice. Immunostaining, flow cytometry, behavioral assay, in vivoimaging were utilized. Results: EA ameliorated mechanical and cold pain hypersensitivities, reduced sensory neuron damage and improved loss in intra-epidermal nerve fibers (IENFs) in model mice. Macrophage infiltration was observed in DRG and sciatic nerve of model mice, which was reduced by EA. EA affected M1-like pro-inflammatory macrophage infiltration in DRG, whereas it did not affect M2-like macrophages. DRG neurons released chemoattractant CCL2 that recruited macrophages via CCR2 to DRG. EA reduced CCL2 overproduction by DRG neurons and reduced macrophage infiltration. Blocking CCR2 mimicked EA’s anti-allodynic effect, whereas exogenously applying CCL2 reversed ameliorating effect of EA on macrophage infiltration and abolished EA’s anti-allodynia on model mice. EA ameliorated other signs of PIPN, including sensory neuron damage, sciatic nerve morphology impairment and IENFs loss. In mice inoculated with breast cancer cells, EA didn’t affect paclitaxel-induced antitumor effect. Conclusions: These findings suggest EA alleviates PIPN by reducing pro-inflammatory macrophage infiltration in sensory ganglia and sciatic nerve. Our study supports acupuncture to be used as a non-pharmacological therapy for PIPN.