title: CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.
abstract: Painful peripheral neuropathy is a dose-limiting side effect of paclitaxel therapy, which hampers the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms remain largely unknown. Here we showed that the clinically relevant dose of paclitaxel (3×8mg/kg, cumulative dose 24mg/kg) induced significant upregulation of the chemokine CX3CL1 in the A-fiber primary sensory neurons in vivo and in vitro and infiltration of macrophages into the dorsal root ganglion (DRG) in rats. Paclitaxel treatment also increased cleaved caspase-3 expression, induced the loss of primary afferent terminal fibers and decreased sciatic-evoked A-fiber responses in the spinal dorsal horn, indicating DRG neuronal apoptosis induced by paclitaxel. In addition, the paclitaxel-induced DRG neuronal apoptosis occurred exclusively in the presence of macrophage in vitro study. Intrathecal or systemic injection of CX3CL1 neutralizing antibody blocked paclitaxel-induced macrophage recruitment and neuronal apoptosis in the DRG, and also attenuated paclitaxel-induced allodynia. Furthermore, depletion of macrophage by systemic administration of clodronate inhibited paclitaxel-induced allodynia. Blocking CX3CL1 decreased activation of p38 MAPK in the macrophage, and inhibition of p38 MAPK activity blocked the neuronal apoptosis and development of mechanical allodynia induced by paclitaxel. These findings provide novel evidence that CX3CL1-recruited macrophage contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy.
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: Cui-Cui
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: He-Quan
authors.initials: HQ
authors.lastname: Zhu
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China.
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Rd. 2, 510080, China. Electronic address: xinwj@mail.sysu.edu.cn.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity*; D010146:Pain / Q000139:chemically induced; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries; D015854:Up-Regulation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; D017239:Paclitaxel
keywords: Allodynia; Apoptosis; CX3CL1; Macrophage; Paclitaxel; p38 MAPK