NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

Journal of Neuroinflammation

Bo Li¹  Yuan-Jie Chen¹  Yan Meng¹  Yuan-Chang Xiong¹  Dai Li¹  Xiang-Zhong Zhang²  Yu-Xuan Luo²  Yan-Ling Yang²  Meng Liu³  Su-Bo Zhang³  Wen-Jun Xin³  Rui-Xian Guo⁴ 

[1] Department of Anesthesiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, 200433, Shanghai, China;Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, 510630, Guangzhou, China;Neuroscience Program, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, 510080, Guangzhou, China;Neuroscience Program, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, 510080, Guangzhou, China;Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-Sen University, 74 Zhongshan Road 2, 510080, Guangzhou, China;

关键词: Paclitaxel;    NFATc2;    CXCL14;    Histone acetylation;    Neuropathic pain;   

DOI  :  10.1186/s12974-020-01992-1

来源: Springer

【 摘 要 】

BackgroundThe major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified.MethodsPaw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism.ResultsWe found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment.We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel.ConclusionThese results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

【 授权许可】

CC BY