Chen Li-Hsien, Yeh Yu-Min, Chen Yi-Fan, Hsu Yu-Hsiang, Wang Hsiao-Hsuan, Lin Peng-Chan, Chang Lian-Yun, Lin Chou-Ching K, Chang Ming-Shi, Shen Meng-Ru
Department of Pharmacology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.
Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.
Pain. 2020 Jun;161(6):1237-1254. doi: 10.1097/j.pain.0000000000001831.
The role of immune mediators, including proinflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here, we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel upregulated IL-20 through dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.
包括促炎细胞因子在内的免疫介质在化疗诱导的周围神经病变（CIPN）中的作用仍不清楚。在此，我们研究了白细胞介素-20（IL-20）在紫杉醇诱导的周围神经病变发生中的作用。化疗癌症患者血清中IL-20水平升高伴随着CIPN风险增加。在小鼠模型中，血清和背根神经节中促炎IL-20水平随紫杉醇治疗而波动。用中和抗体阻断IL-20或其受体的基因缺失可预防CIPN，减轻周围神经损伤，并抑制炎症反应，包括巨噬细胞浸润和细胞因子释放。机制上，紫杉醇通过钙稳态失调上调IL-20，从而增强化疗诱导的神经毒性。重要的是，抑制IL-20在体外和体内均未改变紫杉醇对癌症治疗的疗效。总之，靶向IL-20通过抑制神经炎症和恢复钙稳态来改善紫杉醇诱导的周围神经病变。因此，抗IL-20单克隆抗体是预防和治疗紫杉醇诱导的神经病变的一种有前景的疗法。
